Hot off the presses! Jul 19 Dev Cell

The Jul 19 issue of the Dev Cell is now up on Pubget (About Dev Cell): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• A Decade of Developmental Cell
  - Dev Cell 21(1):1 (2011)
  
• Shifting Patterns: Merging Molecules, Morphogens, Motility, and Methodology
  - Dev Cell 21(1):2-4 (2011)
  We highlight crucial technological progress of the past ten years that permits quantitative analysis of cellular behavior. Adapting these methods to the study of embryogenesis will be essential to advance our understanding of development in the coming decade.
• Bridging Structure and Process in Developmental Biology through New Imaging Technologies
  - Dev Cell 21(1):5-10 (2011)
  Many unexpected discoveries in developmental biology have depended on advancement of imaging technologies to visualize developmental processes as they unfold across multiple spatial and temporal scales. This essay surveys the recent advances in imaging, highlighting emerging capabilities with an eye toward those poised to have the greatest impact on developmental biology.
• Can a Systems Perspective Help Us Appreciate the Biological Meaning of Small Effects?
  - Dev Cell 21(1):11-13 (2011)
  The study of dramatic phenotypes has been pivotal to elucidating biological mechanisms. Effectively approaching low-magnitude quantitative phenotypes, a common outcome of systematic loss-of-function studies, will be critical for understanding how individual components of cells interact to generate functioning systems.
• Beyond Stereospecificity: Liquids and Mesoscale Organization of Cytoplasm
  - Dev Cell 21(1):14-16 (2011)
  The cytoplasm is not a homogenous solution but instead consists of large dynamic assemblies that arise from transient molecular interactions. Some of these structures have been shown to represent liquid droplets of concentrated protein and RNA. Liquid phase separation of cytoplasm may be a fundamental principle of cytoplasmic organization.
• Enhancers: From Developmental Genetics to the Genetics of Common Human Disease
  - Dev Cell 21(1):17-19 (2011)
  In mammals, long-range gene regulation became apparent through simple Mendelian disease genetics in human and developmental genetics in the mouse. Can the insights into gene control, provided by the study of these enhancers, help us understand the functional significance of sequence variation associated with common/complex human disease and quantitative traits?
• The Impact of Developmental Biology on Pluripotent Stem Cell Research: Successes and Challenges
  - Dev Cell 21(1):20-23 (2011)
  Research on developmental pathways in model organisms provides key information on how to isolate, maintain, and differentiate human pluripotent stem cells. However, details of developmental pathways differ even across mammalian species. Full realization of the potential of stem cells will require more direct studies of human or primate developmental biology.
• Self-Organization of Animal Tissues: Cadherin-Mediated Processes
  - Dev Cell 21(1):24-26 (2011)
  Animal cells are capable of self-organizing into multicellular tissues, and important players in this process are cadherin receptors. Through the homophilic interactions of cadherins, cells adhere to one another. Cells can also dynamically change shapes or positions within tissue layers via cadherin-cytoskeleton interactions and become arranged into various architectures.
• Taking a Developmental Perspective on Systems Biology
  - Dev Cell 21(1):27-28 (2011)
  Developmental biologists understand how different cells contribute to organ function and how cellular components work together to produce a phenotype. These insights need to be more widely applied to systems biology. Another challenge is to incorporate real-time imaging and develop computational approaches to model biological phenomena in four dimensions.
• Drosophila as a Model for Interorgan Communication: Lessons from Studies on Energy Homeostasis
  - Dev Cell 21(1):29-31 (2011)
  Current studies of physiological communication between Drosophila organs are beginning to address the fundamental problem of how nutrients regulate organismal growth, stem cell behavior, immunity, and aging. Advances in the Drosophila genetic tool kit will allow the design of genetic screens to systematically identify factors involved in organ communication.
• Protein Evolution in Cell and Tissue Development: Going Beyond Sequence and Transcriptional Analysis
  - Dev Cell 21(1):32-34 (2011)
  Studies of animal evolution often focus on sequence and transcriptional analysis, based on an assumption that the evolution of development is driven by changes in gene expression. We argue that biochemical and cell biological approaches are also required, because sequence-conserved proteins can have different biochemical, cellular, and developmental properties.
• A Hitchhiker's Guide to Mechanobiology
  - Dev Cell 21(1):35-47 (2011)
  More than a century ago, it was proposed that mechanical forces could drive tissue formation. However, only recently with the advent of enabling biophysical and molecular technologies are we beginning to understand how individual cells transduce mechanical force into biochemical signals. In turn, this knowledge of mechanotransduction at the cellular level is beginning to clarify the role of mechanics in patterning processes during embryonic development. In this perspective, we will discuss current mechanotransduction paradigms, along with the technologies that have shaped the field of mechanobiology.
• Forward and Reverse Genetic Approaches for the Analysis of Vertebrate Development in the Zebrafish
  - Dev Cell 21(1):48-64 (2011)
  The development of facile forward and reverse genetic approaches has propelled the deconvolution of gene function in biology. While the origins of these techniques reside in the study of single-cell or invertebrate organisms, in many cases these approaches have been applied to vertebrate model systems to gain powerful insights into gene function during embryonic development. This perspective provides a summary of the major forward and reverse genetic approaches that have contributed to the study of vertebrate gene function in zebrafish, which has become an established model for the study of animal development.
• Developmental Genetics and New Sequencing Technologies: The Rise of Nonmodel Organisms
  - Dev Cell 21(1):65-76 (2011)
  Much of developmental biology in the past decades has been driven by forward genetic studies in a few model organisms. We review recent work with relatives of these species, motivated by a desire to understand the evolutionary and ecological context for morphological innovation. Unfortunately, despite a number of shining examples, progress in nonmodel systems has often been slow. The current revolution in DNA sequencing has, however, enormous potential in extending the reach of genetics. We discuss how developmental biology will benefit from these advances, particularly by increasing the universe of study species.
• The ESCRT Pathway
  - Dev Cell 21(1):77-91 (2011)
  Multivesicular bodies (MVBs) deliver cargo destined for degradation to the vacuole or lysosome. The ESCRT (endosomal sorting complex required for transport) pathway is a key mediator of MVB biogenesis, but it also plays critical roles in retroviral budding and cytokinetic abscission. Despite these diverse roles, the ESCRT pathway can be simply seen as a cargo-recognition and membrane-sculpting machine viewable from three distinct perspectives: (1) the ESCRT proteins themselves, (2) the cargo they sort, and (3) the membrane they deform. Here, we review ESCRT function from these perspectives and discuss how ESCRTs may drive vesicle budding.
• Mitochondria in Apoptosis: Bcl-2 Family Members and Mitochondrial Dynamics
  - Dev Cell 21(1):92-101 (2011)
  Mitochondria participate in apoptosis through a range of mechanisms that vary between vertebrates and invertebrates. In vertebrates, they release intermembrane space proteins, such as cytochrome c, to promote caspase activation in the cytosol. This process is the result of the loss of integrity of the outer mitochondrial membrane caused by proapoptotic members of the Bcl-2 family. This event is always accompanied by a fissioning of the organelle. Fission of mitochondria has also been reported to participate in apoptosis in Drosophila and Caenorhabditis elegans. However, in these organisms, mitochondrial membrane permeabilization does not occur and the mechanism by which mitochondrial dynamics participates in cell death remains elusive.
• Mitotic Spindle Orientation in Asymmetric and Symmetric Cell Divisions during Animal Development
  - Dev Cell 21(1):102-119 (2011)
  The orientation of the mitotic spindle has been proposed to control cell fate choices, tissue architecture, and tissue morphogenesis. Here, we review the mechanisms regulating the orientation of the axis of division and cell fate choices in classical models of asymmetric cell division. We then discuss the mechanisms of mitotic spindle orientation in symmetric cell divisions and its possible implications in tissue morphogenesis. Many recent studies show that future advances in the field of mitotic spindle orientation will arise from combinations of physical perturbation and modeling with classical genetics and developmental biology approaches.
• Planar Cell Polarity: Coordinating Morphogenetic Cell Behaviors with Embryonic Polarity
  - Dev Cell 21(1):120-133 (2011)
  Planar cell polarization entails establishment of cellular asymmetries within the tissue plane. An evolutionarily conserved planar cell polarity (PCP) signaling system employs intra- and intercellular feedback interactions between its core components, including Frizzled, Van Gogh, Flamingo, Prickle, and Dishevelled, to establish their characteristic asymmetric intracellular distributions and coordinate planar polarity of cell populations. By translating global patterning information into asymmetries of cell membranes and intracellular organelles, PCP signaling coordinates morphogenetic behaviors of individual cells and cell populations with the embryonic polarity. In vertebrates, by polarizing cilia in the node/Kupffer's vesicle, PCP signaling links the anteroposterior to left-right embryonic polarity.
• Notch Ligand Ubiquitylation: What Is It Good For?
  - Dev Cell 21(1):134-144 (2011)
  In the first volume of Developmental Cell, it was reported that the classic Drosophila neurogenic gene neuralized encodes a ubiquitin ligase that monoubiquitylates the Notch ligand Delta, thus promoting Delta endocytosis. A requirement for ligand internalization by the signal-sending cell, although counterintuitive, remains to date a feature unique to Notch signaling. Ten years and many ubiquitin ligases later, we discuss sequels to these three papers with an eye toward reviewing the development of ideas for how ligand ubiquitylation and endocytosis propel Notch signaling.
• Extracellular Movement of Signaling Molecules
  - Dev Cell 21(1):145-158 (2011)
  Extracellular signaling molecules have crucial roles in development and homeostasis, and their incorrect deployment can lead to developmental defects and disease states. Signaling molecules are released from sending cells, travel to target cells, and act over length scales of several orders of magnitude, from morphogen-mediated patterning of small developmental fields to hormonal signaling throughout the organism. We discuss how signals are modified and assembled for transport, which routes they take to reach their targets, and how their range is affected by mobility and stability.
• Drosophila Stem Cell Niches: A Decade of Discovery Suggests a Unified View of Stem Cell Regulation
  - Dev Cell 21(1):159-171 (2011)
  The past decade of research on Drosophila stem cells and niches has provided key insights. Fly stem cells do not occupy a special "state" based on novel "stem cell genes" but resemble transiently arrested tissue progenitors. Moreover, individual stem cells and downstream progenitors are highly dynamic and dispensable, not tissue bulwarks. Niches, rather than fixed cell lineages, ensure tissue health by holding stem cells and repressing cell differentiation inside, but not outside. We review the five best-understood adult Drosophila stem cells and argue that the fundamental biology of stem cells and niches is conserved between Drosophila and mice.
• The Cellular Basis for Animal Regeneration
  - Dev Cell 21(1):172-185 (2011)
  The ability of animals to regenerate missing parts is a dramatic and poorly understood aspect of biology. The sources of new cells for these regenerative phenomena have been sought for decades. Recent advances involving cell fate tracking in complex tissues have shed new light on the cellular underpinnings of regeneration in Hydra, planarians, zebrafish, Xenopus, and Axolotl. Planarians accomplish regeneration with use of adult pluripotent stem cells, whereas several vertebrates utilize a collection of lineage-restricted progenitors from different tissues. Together, an array of cellular strategies—from pluripotent stem cells to tissue-specific stem cells and dedifferentiation—are utilized for regeneration.

Hot off the presses! Nov 16 dev cell

The Nov 16 issue of the dev cell is now up on Pubget (About dev cell): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• Myosin-II Puts the Squeeze on Asymmetric Cell Division
  - dev cell 19(5):639-640 (2010)
  Asymmetric cell division—where two dissimilar daughter cells are produced—relies on asymmetric positioning of the telophase spindle midzone, which specifies the cleavage furrow. Ou et al. (2010) now report in Science a mechanism of asymmetric midzone positioning driven by a polarized cortical distribution of the contractile motor myosin-II.
• Targeting p21 Degradation Locally
  - dev cell 19(5):641-643 (2010)
  Just as the activity of many multifunctional proteins is restricted by subcellular localization, so is their regulation. In this issue of Development Cell, Starostina et al. identify an E3 ubiquitin ligase, CRL2LRR1, for the cyclin-dependent kinase inhibitor p21 that specifically ubiquitylates cytoplasmic p21 to facilitate cell migration.
• Anthrax Toxins—Roadblocks for Exocytic Trafficking
  - dev cell 19(5):643-644 (2010)
  Anthrax toxins cause vascular dysfunction, in part by perturbing the endothelial cell barrier. Reporting in Nature, Guichard et al. shed new light on the mechanism by which this occurs and show that anthrax toxins interfere with exocytic delivery of cadherins to endothelial cell junctions by antagonizing the exocyst complex.
• Feeling UPBEAT about Growth: Linking ROS Gradients and Cell Proliferation
  - dev cell 19(5):644-646 (2010)
  Recent work in animals and plants suggests that reactive oxygen species (ROS) control cell proliferation. Reporting in Cell, Tsukagoshi et al. (2010) identify UPBEAT1 as a key transcription factor in the regulation of ROS distribution, which they find controls the transition between cell proliferation and differentiation in the Arabidopsis root.
• Global Approaches to Identify Novel Participants that Modulate Intestinal Epithelial Cell Development
  - dev cell 19(5):647-648 (2010)
  Combinatorial control of lineage-specific gene expression is commonly mediated by suites of diverse transcriptional regulators. In this issue of Developmental Cell, Verzi et al. (2010) use an unbiased global and computational approach to identify distinct partners and functions of CDX2 in intestinal epithelial cell differentiation.
• Tuning In to Noise: Epigenetics and Intangible Variation
  - dev cell 19(5):649-650 (2010)
  In this special issue of Developmental Cell, we discuss the role of chromatin in phenotypic variation as a counterpoint to the reviews on chromatin dynamics in development and cancer. We highlight some recent work on the role of chromatin in transcriptional noise in yeast and Caenorhabditis elegans and consider the implications in understanding intangible variation or developmental noise in mammals.
• Interpretation of Developmental Signaling at Chromatin: The Polycomb Perspective
  - dev cell 19(5):651-661 (2010)
  The Polycomb group (PcG) system represses the transcription of important developmental regulators and perpetuates this repression across multiple cell divisions. Inputs from outside the cell can influence PcG function by recruiting additional chromatin factors to PcG-regulated loci or by downregulating the PcG genes themselves. These types of PcG system modulation allow context-dependent induction of genes during development, in cancer, and in response to changes in the environment. In this review, we outline instances where molecular players in this process have been recently identified, comparing and contrasting different ways in which derepression is achieved, and projecting directions for future research.
• Histone Variants in Metazoan Development
  - dev cell 19(5):662-674 (2010)
  Embryonic development is regulated by both genetic and epigenetic mechanisms, with nearly all DNA-templated processes influenced by chromatin architecture. Sequence variations in histone proteins, core components of chromatin, provide a means to generate diversity in the chromatin structure, resulting in distinct and profound biological outcomes in the developing embryo. Emerging literature suggests that epigenetic contributions from histone variants play key roles in a number of developmental processes such as the initiation and maintenance of pericentric heterochromatin, X-inactivation, and germ cell differentiation. Here, we review the role of histone variants in the embryo with particular emphasis on early mammalian development.
• Epigenetic Transitions in Germ Cell Development and Meiosis
  - dev cell 19(5):675-686 (2010)
  Germ cell development is controlled by unique gene expression programs and involves epigenetic reprogramming of histone modifications and DNA methylation. The central event is meiosis, during which homologous chromosomes pair and recombine, processes that involve histone alterations. At unpaired regions, chromatin is repressed by meiotic silencing. After meiosis, male germ cells undergo chromatin remodeling, including histone-to-protamine replacement. Male and female germ cells are also differentially marked by parental imprints, which contribute to sex determination in insects and mediate genomic imprinting in mammals. Here, we review epigenetic transitions during gametogenesis and discuss novel insights from animal and human studies.
• Small RNA-Mediated Quiescence of Transposable Elements in Animals
  - dev cell 19(5):687-697 (2010)
  Transposable elements (TEs) are major components of the intergenic regions of the genome. However, TE transposition has the potential to threaten the reproductive fitness of the organism; therefore, organisms have evolved specialized molecular systems to sense and repress the expression of TEs to stop them from jumping to other genomic loci. Emerging evidence suggests that Argonaute proteins play a critical role in this process, in collaboration with two types of cellular small RNAs: PIWI-interacting RNAs (piRNAs) of the germline and endogenous small interfering RNAs (endo-siRNAs) of the soma, both of which are transcribed from TEs themselves.
• Aberrant Epigenetic Landscape in Cancer: How Cellular Identity Goes Awry
  - dev cell 19(5):698-711 (2010)
  Appropriate patterns of DNA methylation and histone modifications are required to assure cell identity, and their deregulation can contribute to human diseases, such as cancer. Our aim here is to provide an overview of how epigenetic factors, including genomic DNA methylation, histone modifications, and microRNA regulation, contribute to normal development, paying special attention to their role in regulating tissue-specific genes. In addition, we summarize how these epigenetic patterns go awry during human cancer development. The possibility of "resetting" the abnormal cancer epigenome by applying pharmacological or genetic strategies is also discussed.
• Differentiation-Specific Histone Modifications Reveal Dynamic Chromatin Interactions and Partners for the Intestinal Transcription Factor CDX2
  - dev cell 19(5):713-726 (2010)
  Cell differentiation requires remodeling of tissue-specific gene loci and activities of key transcriptional regulators, which are recognized for their dominant control over cellular programs. Using epigenomic methods, we characterized enhancer elements specifically modified in differentiating intestinal epithelial cells and found enrichment of transcription factor-binding motifs corresponding to CDX2, a critical regulator of the intestine. Directed investigation revealed surprising lability in CDX2 occupancy of the genome, with redistribution from hundreds of sites occupied only in proliferating cells to thousands of new sites in differentiated cells. Knockout mice confirmed distinct Cdx2 requirements in dividing and mature adult intestinal cells, including responsibility for the active enhancer configuration associated with maturity. Dynamic CDX2 occupancy corresponds with condition-specific gene expression and, importantly, to differential co-occupancy with other tis! sue-restricted transcription factors, such as GATA6 and HNF4A. These results reveal dynamic, context-specific functions and mechanisms of a prominent transcriptional regulator within a cell lineage. Video Abstract To view the video inline, enable JavaScript on your browser. However, you can download and view the video by clicking on the icon below Download this Video (20899 K)
• The NF2 Tumor Suppressor, Merlin, Regulates Epidermal Development through the Establishment of a Junctional Polarity Complex
  - dev cell 19(5):727-739 (2010)
  The neurofibromatosis type 2 (NF2) tumor suppressor, Merlin, is a FERM (Four point one, Ezrin, Radixin, Moesin) domain-containing protein whose loss results in defective morphogenesis and tumorigenesis in multiple tissues. Like the closely related ERM proteins (Ezrin, Radixin, and Moesin), Merlin may organize the plasma membrane by assembling membrane protein complexes and linking them to the cortical actin cytoskeleton. We previously found that Merlin is a critical mediator of contact-dependent inhibition of proliferation and is required for the establishment of stable adherens junctions (AJs) in cultured cells. Here, we delineate the molecular function of Merlin in AJ establishment in epidermal keratinocytes in vitro and confirm that a role in AJ establishment is an essential function of Merlin in vivo. Our studies reveal that Merlin can associate directly with α-catenin and link it to Par3, thereby providing an essential link between the AJ and the Par3 polarity co! mplex during junctional maturation.
• The Fz-Dsh Planar Cell Polarity Pathway Induces Oriented Cell Division via Mud/NuMA in Drosophila and Zebrafish
  - dev cell 19(5):740-752 (2010)
  The Frizzled receptor and Dishevelled effector regulate mitotic spindle orientation in both vertebrates and invertebrates, but how Dishevelled orients the mitotic spindle is unknown. Using the Drosophila S2 cell "induced polarity" system, we find that Dishevelled cortical polarity is sufficient to orient the spindle and that Dishevelled's DEP domain mediates this function. This domain binds a C-terminal domain of Mud (the Drosophila NuMA ortholog), and Mud is required for Dishevelled-mediated spindle orientation. In Drosophila, Frizzled-Dishevelled planar cell polarity (PCP) orients the sensory organ precursor (pI) spindle along the anterior-posterior axis. We show that Dishevelled and Mud colocalize at the posterior cortex of pI, Mud localization at the posterior cortex requires Dsh, and Mud loss-of-function randomizes spindle orientation. During zebrafish gastrulation, the Wnt11-Frizzled-Dishevelled PCP pathway orients spindles along the animal-vegetal axis, and ! reducing NuMA levels disrupts spindle orientation. Overall, we describe a Frizzled-Dishevelled-NuMA pathway that orients division from Drosophila to vertebrates.
• CRL2LRR-1 Targets a CDK Inhibitor for Cell Cycle Control in C. elegans and Actin-Based Motility Regulation in Human Cells
  - dev cell 19(5):753-764 (2010)
  The Cip/Kip CDK inhibitor (CKI) p21Cip1/WAF1 has a critical role in the nucleus to limit cell proliferation by inhibiting CDK-cyclin complexes. In contrast, cytoplasmic p21 regulates cell survival and the actin cytoskeleton. These divergent functions for p21 in different cellular compartments suggest the necessity for complex regulation. In this study, we identify the CRL2LRR-1 ubiquitin ligase as a conserved regulator of Cip/Kip CKIs that promotes the degradation of C. elegans CKI-1 and human p21. The nematode CRL2LRR-1 complex negatively regulates nuclear CKI-1 levels to ensure G1-phase cell cycle progression in germ cells. In contrast, human CRL2LRR1 targets cytoplasmic p21, acting as a critical regulator of cell motility that promotes a nonmotile stationary cell state by preventing p21 from inhibiting the Rho/ROCK/LIMK pathway. Inactivation of human CRL2LRR1 leads to the activation of the actin-depolymerizing protein cofilin, dramatic reorganization of the actin cy! toskeleton, and increased cell motility.
• Integration of Brassinosteroid Signal Transduction with the Transcription Network for Plant Growth Regulation in Arabidopsis
  - dev cell 19(5):765-777 (2010)
  Brassinosteroids (BRs) regulate a wide range of developmental and physiological processes in plants through a receptor-kinase signaling pathway that controls the BZR transcription factors. Here, we use transcript profiling and chromatin-immunoprecipitation microarray (ChIP-chip) experiments to identify 953 BR-regulated BZR1 target (BRBT) genes. Functional studies of selected BRBTs further demonstrate roles in BR promotion of cell elongation. The BRBT genes reveal numerous molecular links between the BR-signaling pathway and downstream components involved in developmental and physiological processes. Furthermore, the results reveal extensive crosstalk between BR and other hormonal and light-signaling pathways at multiple levels. For example, BZR1 not only controls the expression of many signaling components of other hormonal and light pathways but also coregulates common target genes with light-signaling transcription factors. Our results provide a genomic map of steroi! d hormone actions in plants that reveals a regulatory network that integrates hormonal and light-signaling pathways for plant growth regulation.
• Interplay between the Transcription Factor Zif and aPKC Regulates Neuroblast Polarity and Self-Renewal
  - dev cell 19(5):778-785 (2010)
  How a cell decides to self-renew or differentiate is a critical issue in stem cell and cancer biology. Atypical protein kinase C (aPKC) promotes self-renewal of Drosophila larval brain neural stem cells, neuroblasts. However, it is unclear how aPKC cortical polarity and protein levels are regulated. Here, we have identified a zinc-finger protein, Zif, which is required for the expression and asymmetric localization of aPKC. aPKC displays ectopic cortical localization with upregulated protein levels in dividing zif mutant neuroblasts, leading to neuroblast overproliferation. We show that Zif is a transcription factor that directly represses aPKC transcription. We further show that Zif is phosphorylated by aPKC both in vitro and in vivo. Phosphorylation of Zif by aPKC excludes it from the nucleus, leading to Zif inactivation in neuroblasts. Thus, reciprocal repression between Zif and aPKC act as a critical regulatory mechanism for establishing cell polarity and controlli! ng neuroblast self-renewal.

Hot off the presses! Oct 18 Dev Cell

The Oct 18 issue of the Dev Cell is now up on Pubget (About Dev Cell): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• Deciphering Gene Expression Patterns
  - Dev Cell 21(4):e1 (2011)
  Large-scale studies in various model systems including Drosophila, fish, and the mouse have documented the exquisite temporal and spatial expression patterns of thousands of genes during development—making sense of it all is a major challenge in the field. The study by Yakoby and colleagues illustrates how very different expression patterns can be generated from a small number of initial patterns. By examining expression patterns for a large number of genes in the Drosophila follicle cell epithelium, the authors proposed that the various expression patterns could be explained by a simple combinatorial code based on six spatial building blocks and the operations of union, difference, intersection, and addition. Importantly, the six spatial building blocks can be linked to the activity of the epidermal growth factor receptor and bone morphogenetic protein signaling pathways that control gene expression along the dorsoventral and anteroposterior axes. A challenge for th! e future will be to see whether such a powerful approach can be applied to explain the diversity of patterns generated in more complex systems such as embryos. This PaperPick refers to "A Combinatorial Code for Pattern Formation in Drosophila Oogenesis" by N. Yakoby, C.A. Bristow, D. Gong, X. Schafer, J. Lembong, J.J. Zartman, M.S. Halfon, T. Schüpbach, and S.Y. Shvartsman, published in November 2008. Video Abstract
• Endoderm Formation: Not So Black and White Anymore
  - Dev Cell 21(4):e2 (2011)
  This study illustrates how the combination of innovative genetic mouse models, embryological experimentation, and live-imaging techniques can resolve longstanding questions in endoderm formation during early mouse development. Kwon et al. showed that cells recruited from the epiblast during germ layer formation in the mouse embryo are not always incorporated into the endoderm in the immediate vicinity of the primitive streak. Beyond demonstrating that the mouse is just like a chick in its strategy for definitive (gut) endoderm recruitment, this finding resolved the enigmatic observation that some epiblast-derived cells in the endoderm are localized further from the site of ingression than anticipated based on "conventional" wisdom. Through tracking of the distribution of the visceral endoderm pre-existing prior to gastrulation, descendants of the visceral endoderm were found, surprisingly, to colonize the embryonic gut, thus dispelling the myth that visceral endode! rm differs from the so-called "definitive" endoderm in its inability to contribute to the embryonic gut and that it is replaced wholesale by the nascent population recruited during gastrulation. This paper thus delineated a paradigm of mouse endoderm formation and presented us with the challenge of determining the ultimate fates of these visceral endoderm cells in the fetal and adult gut. This PaperPick refers to "The Endoderm of the Mouse Embryo Arises by Dynamic Widespread Intercalation of Embryonic and Extraembryonic Lineages," by G.S. Kwon, M. Viotti, and A.K. Hadjantonakis, published in October 2008. Video Abstract
• MINOS Is Plus: A Mitofilin Complex for Mitochondrial Membrane Contacts
  - Dev Cell 21(4):599-600 (2011)
  Cristae junctions mark the boundaries of respiratory compartments in the inner mitochondrial membrane. In this issue of Developmental Cell, identify a complex, MINOS, that organizes cristae junctions. Mitofilin/Fcj1, the central component of the MINOS complex, also connects the inner membrane to outer membrane protein import machinery.
• Cyclin beyond the Cell Cycle: New Partners at the Synapse
  - Dev Cell 21(4):601-602 (2011)
  In this issue of Developmental Cell, demonstrate that the cell-cycle regulator, cyclin E, sequesters Cdk5, a key regulator of neuronal development and synaptic plasticity. This cell-cycle-independent function of cyclin E reveals an exciting mode of Cdk5 regulation in postmitotic neurons and offers a window into evolutionary parsimony.
• The Hormone of Love Attracts a Partner for Life
  - Dev Cell 21(4):602-604 (2011)
  Neurovascular integration during embryonic development is essential for adult physiology. In this issue of Developmental Cell, report that hypothalamic neurons secrete oxytocin as a guidance cue for endothelial cells to establish their vascular supplyâ€"a prerequisite for neuroendocrine secretion from the neurohyophysis in adult life.
• Long, Saturated Chains: Tasty Domains for Kinases of Insulin Resistance
  - Dev Cell 21(4):604-606 (2011)
  The mechanistic basis of how cells respond to increased fatty acids (FAs) is murky but potentially involves receptor-mediated activation or inhibition by different FA classes. recently propose in Cell that expansion of intracellular membrane microdomains induced by saturated FA recruit and activate c-Src for JNK activation.
• Squeezing into Differentiation
  - Dev Cell 21(4):607-608 (2011)
  The earliest steps in tooth development depend on signaling interactions that result in the condensation of mandibular mesenchyme into the tooth bud. Reporting in this issue of Developmental Cell, find that chemotactic signals coordinate condensation and that the compressive force generated is sufficient to induce tooth bud gene expression.
• Bypassing Transcription: A Shortcut in Cytokinin-Auxin Interactions
  - Dev Cell 21(4):608-610 (2011)
  In this issue of Developmental Cell, uncover a transcription-independent molecular mechanism of interaction between auxin and cytokinin in the regulation of plant meristem function. By modulating endocytic trafficking of PIN1, cytokinin controls auxin flux and, therefore, auxin gradients.
• Animal Transcription Networks as Highly Connected, Quantitative Continua
  - Dev Cell 21(4):611-626 (2011)
  To understand how transcription factors function, it is essential to determine the range of genes that they each bind and regulate in vivo. Here I review evidence that most animal transcription factors each bind to a majority of genes over a quantitative series of DNA occupancy levels. These continua span functional, quasifunctional, and nonfunctional DNA binding events. Factor regulatory specificities are distinguished by quantitative differences in DNA occupancy patterns. I contrast these results with models for transcription networks that define discrete sets of direct target and nontarget genes and consequently do not fully capture the complexity observed in vivo.
• A Conserved Pbx-Wnt-p63-Irf6 Regulatory Module Controls Face Morphogenesis by Promoting Epithelial Apoptosis
  - Dev Cell 21(4):627-641 (2011)
  Morphogenesis of mammalian facial processes requires coordination of cellular proliferation, migration, and apoptosis to develop intricate features. Cleft lip and/or palate (CL/P), the most frequent human craniofacial birth defect, can be caused by perturbation of any of these programs. Mutations of WNT, P63, and IRF6 yield CL/P in humans and mice; however, how these genes are regulated remains elusive. We generated mouse lines lacking Pbx genes in cephalic ectoderm and demonstrated that they exhibit fully penetrant CL/P and perturbed Wnt signaling. We also characterized a midfacial regulatory element that Pbx proteins bind to control the expression of Wnt9b-Wnt3, which in turn regulates p63. Altogether, we establish a Pbx-dependent Wnt-p63-Irf6 regulatory module in midfacial ectoderm that is conserved within mammals. Dysregulation of this network leads to localized suppression of midfacial apoptosis and CL/P. Ectopic Wnt ectodermal expression in Pbx mutants rescues th! e clefting, opening avenues for tissue repair.
• The Hypothalamic Neuropeptide Oxytocin Is Required for Formation of the Neurovascular Interface of the Pituitary
  - Dev Cell 21(4):642-654 (2011)
  The hypothalamo-neurohypophyseal system (HNS) is the neurovascular structure through which the hypothalamic neuropeptides oxytocin and arginine-vasopressin exit the brain into the bloodstream, where they go on to affect peripheral physiology. Here, we investigate the molecular cues that regulate the neurovascular contact between hypothalamic axons and neurohypophyseal capillaries of the zebrafish. We developed a transgenic system in which both hypothalamic axons and neurohypophyseal vasculature can be analyzed in vivo. We identified the cellular organization of the zebrafish HNS as well as the dynamic processes that contribute to formation of the HNS neurovascular interface. We show that formation of this interface is regulated during development by local release of oxytocin, which affects endothelial morphogenesis. This cell communication process is essential for the establishment of a tight axovasal interface between the neurons and blood vessels of the HNS. We prese! nt a unique example of axons affecting endothelial morphogenesis through secretion of a neuropeptide.
• Cyclin E Constrains Cdk5 Activity to Regulate Synaptic Plasticity and Memory Formation
  - Dev Cell 21(4):655-668 (2011)
  Cyclin E is a component of the core cell cycle machinery, and it drives cell proliferation by regulating entry and progression of cells through the DNA synthesis phase. Cyclin E expression is normally restricted to proliferating cells. However, high levels of cyclin E are expressed in the adult brain. The function of cyclin E in quiescent, postmitotic nervous system remains unknown. Here we use a combination of in vivo quantitative proteomics and analyses of cyclin E knockout mice to demonstrate that in terminally differentiated neurons cyclin E forms complexes with Cdk5 and controls synapse function by restraining Cdk5 activity. Ablation of cyclin E led to a decreased number of synapses, reduced number and volume of dendritic spines, and resulted in impaired synaptic plasticity and memory formation in cyclin E-deficient animals. These results reveal a cell cycle-independent role for a core cell cycle protein, cyclin E, in synapse function and memory.
• MADD-4 Is a Secreted Cue Required for Midline-Oriented Guidance in Caenorhabditis elegans
  - Dev Cell 21(4):669-680 (2011)
  The netrins and slits are two families of widely conserved cues that guide axons and cells along the dorsal-ventral (D-V) axis of animals. These cues typically emanate from the dorsal or ventral midlines and provide spatial information to migrating cells by forming gradients along the D-V axis. Some cell types, however, extend processes to both the dorsal and ventral midlines, suggesting the existence of additional guidance cues that are secreted from both midlines. Here, we report that a previously uncharacterized protein called MADD-4 is secreted by the dorsal and ventral nerve cords of the nematode C. elegans to attract sensory axons and muscle membrane extensions called muscle arms. MADD-4's activity is dependent on UNC-40/DCC, a netrin receptor, which functions cell-autonomously to direct membrane extension. The biological role of MADD-4 orthologs, including ADAMTSL1 and 3 in mammals, is unknown. MADD-4 may therefore represent the founding member of a family of gu! idance proteins.
• A Syndecan-4 Hair Trigger Initiates Wound Healing through Caveolin- and RhoG-Regulated Integrin Endocytosis
  - Dev Cell 21(4):681-693 (2011)
  Cell migration during wound healing requires adhesion receptor turnover to enable the formation and disassembly of cell-extracellular matrix contacts. Although recent advances have improved our understanding of integrin trafficking pathways, it is not known how extracellular ligand engagement controls receptor dynamics. Using atomic force microscopy, we have measured cell avidity for fibronectin and defined a mechanism for the outside-in regulation of α5β1-integrin. Surprisingly, adhesive strength was attenuated by the syndecan-4-binding domain of fibronectin due to a rapid triggering of α5β1-integrin endocytosis. Association of syndecan-4 with PKCα was found to trigger RhoG activation and subsequent dynamin- and caveolin-dependent integrin uptake. Like disruption of syndecan-4 or caveolin, gene disruption of RhoG in mice was found to retard closure of dermal wounds due to a migration defect of the fibroblasts and keratinocytes of RhoG null mice. Thus, this syndec! an-4-regulated integrin endocytic pathway appears to play a key role in tissue repair.
• Dual Role of Mitofilin in Mitochondrial Membrane Organization and Protein Biogenesis
  - Dev Cell 21(4):694-707 (2011)
  The mitochondrial inner membrane consists of two domains, inner boundary membrane and cristae membrane that are connected by crista junctions. Mitofilin/Fcj1 was reported to be involved in formation of crista junctions, however, different views exist on its function and possible partner proteins. We report that mitofilin plays a dual role. Mitofilin is part of a large inner membrane complex, and we identify five partner proteins as constituents of the mitochondrial inner membrane organizing system (MINOS) that is required for keeping cristae membranes connected to the inner boundary membrane. Additionally, mitofilin is coupled to the outer membrane and promotes protein import via the mitochondrial intermembrane space assembly pathway. Our findings indicate that mitofilin is a central component of MINOS and functions as a multifunctional regulator of mitochondrial architecture and protein biogenesis.
• The Tetraspanin CD63 Regulates ESCRT-Independent and -Dependent Endosomal Sorting during Melanogenesis
  - Dev Cell 21(4):708-721 (2011)
  Cargo sorting to intraluminal vesicles (ILVs) of multivesicular endosomes is required for lysosome-related organelle (LRO) biogenesis. PMEL—a component of melanocyte LROs (melanosomes)—is sorted to ILVs in an ESCRT-independent manner, where it is proteolytically processed and assembled into functional amyloid fibrils during melanosome maturation. Here we show that the tetraspanin CD63 directly participates in ESCRT-independent sorting of the PMEL luminal domain, but not of traditional ESCRT-dependent cargoes, to ILVs. Inactivating CD63 in cell culture or in mice impairs amyloidogenesis and downstream melanosome morphogenesis. Whereas CD63 is required for normal PMEL luminal domain sorting, the disposal of the remaining PMEL transmembrane fragment requires functional ESCRTs but not CD63. In the absence of CD63, the PMEL luminal domain follows this fragment and is targeted for ESCRT-dependent degradation. Our data thus reveal a tight interplay regulated by CD63 betwe! en two distinct endosomal ILV sorting processes for a single cargo during LRO biogenesis.
• Rac1 Drives Melanoblast Organization during Mouse Development by Orchestrating Pseudopod- Driven Motility and Cell-Cycle Progression
  - Dev Cell 21(4):722-734 (2011)
  During embryogenesis, melanoblasts proliferate and migrate ventrally through the developing dermis and epidermis as single cells. Targeted deletion of Rac1 in melanoblasts during embryogenesis causes defects in migration, cell-cycle progression, and cytokinesis. Rac1 null cells migrate markedly less efficiently, but surprisingly, global steering, crossing the dermal/epidermal junction, and homing to hair follicles occur normally. Melanoblasts navigate in the epidermis using two classes of protrusion: short stubs and long pseudopods. Short stubs are distinct from blebs and are driven by actin assembly but are independent of Rac1, Arp2/3 complex, myosin, or microtubules. Rac1 positively regulates the frequency of initiation of long pseudopods, which promote migration speed and directional plasticity. Scar/WAVE and Arp2/3 complex drive actin assembly for long pseudopod extension, which also depends on microtubule dynamics. Myosin contractility balances the extension of lo! ng pseudopods by effecting retraction and allowing force generation for movement through the complex 3D epidermal environment.
• Dual Roles for Rac2 in Neutrophil Motility and Active Retention in Zebrafish Hematopoietic Tissue
  - Dev Cell 21(4):735-745 (2011)
  Neutrophil homeostasis is essential for host defense. Here we identify dual roles for Rac2 during neutrophil homeostasis using a zebrafish model of primary immune deficiency induced by the human inhibitory Rac2D57N mutation in neutrophils. Noninvasive live imaging of Rac2 morphants or Rac2D57N zebrafish larvae demonstrates an essential role for Rac2 in regulating 3D motility and the polarization of F-actin dynamics and PI(3)K signaling in vivo. Tracking of photolabeled Rac2-deficient neutrophils from hematopoietic tissue also shows increased mobilization into the circulation, indicating that neutrophil mobilization does not require traditionally defined cell motility. Moreover, excessive neutrophil retention in hematopoietic tissue resulting from a constitutively active CXCR4 mutation in zebrafish warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is partially rescued by the inhibitory Rac2 mutation. These findings reveal that Rac2 signaling is! necessary for both neutrophil 3D motility and CXCR4-mediated neutrophil retention in hematopoietic tissue, thereby limiting neutrophil mobilization, a critical first step in the innate immune response.
• ATXN1 Protein Family and CIC Regulate Extracellular Matrix Remodeling and Lung Alveolarization
  - Dev Cell 21(4):746-757 (2011)
  Although expansion of CAG repeats in ATAXIN1 (ATXN1) causes Spinocerebellar ataxia type 1, the functions of ATXN1 and ATAXIN1-Like (ATXN1L) remain poorly understood. To investigate the function of these proteins, we generated and characterized Atxn1L−/− and Atxn1−/−; Atxn1L−/− mice. Atxn1L−/− mice have hydrocephalus, omphalocele, and lung alveolarization defects. These phenotypes are more penetrant and severe in Atxn1−/−; Atxn1L−/− mice, suggesting that ATXN1 and ATXN1L are functionally redundant. Upon pursuing the molecular mechanism, we discovered that several Matrix metalloproteinase (Mmp) genes are overexpressed and that the transcriptional repressor Capicua (CIC) is destabilized in Atxn1L−/− lungs. Consistent with this, Cic deficiency causes lung alveolarization defect. Loss of either ATXN1L or CIC derepresses Etv4, an activator for Mmp genes, thereby mediating MMP9 overexpression. These findings demonstrate a critical role of ATXN1/ATX! N1L-CIC complexes in extracellular matrix (ECM) remodeling during development and their potential roles in pathogenesis of disorders affecting ECM remodeling.
• Mechanochemical Control of Mesenchymal Condensation and Embryonic Tooth Organ Formation
  - Dev Cell 21(4):758-769 (2011)
  Mesenchymal condensation is critical for organogenesis, yet little is known about how this process is controlled. Here we show that Fgf8 and Sema3f, produced by early dental epithelium, respectively, attract and repulse mesenchymal cells, which cause them to pack tightly together during mouse tooth development. Resulting mechanical compaction-induced changes in cell shape induce odontogenic transcription factors (Pax9, Msx1) and a chemical cue (BMP4), and mechanical compression of mesenchyme is sufficient to induce tooth-specific cell fate switching. The inductive effects of cell compaction are mediated by suppression of the mechanical signaling molecule RhoA, and its overexpression prevents odontogenic induction. Thus, the mesenchymal condensation that drives tooth formation is induced by antagonistic epithelial morphogens that manifest their pattern-generating actions mechanically via changes in mesenchymal cell shape and altered mechanotransduction.
• Cell Identity Regulators Link Development and Stress Responses in the Arabidopsis Root
  - Dev Cell 21(4):770-782 (2011)
  Stress responses in plants are tightly coordinated with developmental processes, but interaction of these pathways is poorly understood. We used genome-wide assays at high spatiotemporal resolution to understand the processes that link development and stress in the Arabidopsis root. Our meta-analysis finds little evidence for a universal stress response. However, common stress responses appear to exist with many showing cell type specificity. Common stress responses may be mediated by cell identity regulators because mutations in these genes resulted in altered responses to stress. Evidence for a direct role for cell identity regulators came from genome-wide binding profiling of the key regulator SCARECROW, which showed binding to regulatory regions of stress-responsive genes. Coexpression in response to stress was used to identify genes involved in specific developmental processes. These results reveal surprising linkages between stress and development at cellular res! olution, and show the power of multiple genome-wide data sets to elucidate biological processes.
• A Muscle-Specific p38 MAPK/Mef2/MnSOD Pathway Regulates Stress, Motor Function, and Life Span in Drosophila
  - Dev Cell 21(4):783-795 (2011)
  Molecular mechanisms that concordantly regulate stress, life span, and aging remain incompletely understood. Here, we demonstrate that in Drosophila, a p38 MAP kinase (p38K)/Mef2/MnSOD pathway is a coregulator of stress and life span. Hence, overexpression of p38K extends life span in a MnSOD-dependent manner, whereas inhibition of p38K causes early lethality and precipitates age-related motor dysfunction and stress sensitivity, that is rescued through muscle-restricted (but not neuronal) add-back of p38K. Additionally, mutations in p38K are associated with increased protein carbonylation and Nrf2-dependent transcription, while adversely affecting metabolic response to hypoxia. Mechanistically, p38K modulates expression of the mitochondrial MnSOD enzyme through the transcription factor Mef2, and predictably, perturbations in MnSOD modify p38K-dependent phenotypes. Thus, our results uncover a muscle-restricted p38K-Mef2-MnSOD signaling module that influences life span a! nd stress, distinct from the insulin/JNK/FOXO pathway. We propose that potentiating p38K might be instrumental in restoring the mitochondrial detoxification machinery and combating stress-induced aging.
• Cytokinin Modulates Endocytic Trafficking of PIN1 Auxin Efflux Carrier to Control Plant Organogenesis
  - Dev Cell 21(4):796-804 (2011)
  Cytokinin is an important regulator of plant growth and development. In Arabidopsis thaliana, the two-component phosphorelay mediated through a family of histidine kinases and response regulators is recognized as the principal cytokinin signal transduction mechanism activating the complex transcriptional response to control various developmental processes. Here, we identified an alternative mode of cytokinin action that uses endocytic trafficking as a means to direct plant organogenesis. This activity occurs downstream of known cytokinin receptors but through a branch of the cytokinin signaling pathway that does not involve transcriptional regulation. We show that cytokinin regulates endocytic recycling of the auxin efflux carrier PINFORMED1 (PIN1) by redirecting it for lytic degradation in vacuoles. Stimulation of the lytic PIN1 degradation is not a default effect for general downregulation of proteins from plasma membranes, but a specific mechanism to rapidly modulat! e the auxin distribution in cytokinin-mediated developmental processes.

Hot off the presses! May 17 dev cell

The May 17 issue of the dev cell is now up on Pubget (About dev cell): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• At the Right Time and at the Right Place: Control of Cytokinesis in Mammals
  - dev cell 20(5):e1 (2011)
  Ensuring that cytokinesis occurs at the right time and in the right place is essential to maintain euploidy and cell-cycle progression. Cytokinesis is triggered by the RhoA GEF Ect2, which localizes to the spindle midzone during anaphase and activates RhoA at the overlying cell cortex to stimulate contractile ring formation. Using a chemical inhibitor of the Polo kinase Plk1, Petronczki et al. (2007) showed that Plk1 is essential for cytokinesis, because it specifically promotes Ect2 localization and interaction with its midzone receptor HsCyk-4. I liked this paper for three reasons. As a biologist, I was impressed because the paper explains an important part of biology: how a cell-cycle kinase determines when and where cytokinesis occurs. As a geneticist, I appreciate a "tight allele." The paper is a beautiful example of the power of chemical genetics to specifically and rapidly inhibit Polo at a specific cell-cycle stage. Finally, as a yeast cell-cycle researcher, it is always nice to see the dramatic conservation between yeast and mammals. In budding yeast, even though the bud neck and not the spindle midzone determines the site of cytokinesis, Polo kinase phosphorylates Rho GEFs to initiate contractile ring formation and cytokinesis. This PaperPick refers to "Polo-like Kinase 1 Triggers the Initiation of Cytokinesis in Human Cells by Promoting Recruitment of the RhoGEF Ect2 to the Central Spindle," by M. Petronczki, M. Glotzer, N. Kraut, and J.-M. Peters, published in May 2007. Video Abstract (20715 K) Here, Jan-Michael Peters discusses the work as a collaboration between Mark Petronczki (in his group), Michael Glotzer of the University of Chicago, and Norbert Kraut of Boehringer Ingelheim, who provided the key reagent: BI 2536, a chemical inhibitor of Plk1. The authors would like to note that their work on the role of Plk1 in cytokinesis was inspired by early observations made in the laboratory of David Glover and that the research groups of Prasad Jallepalli (Sloan Kettering) and Aaron Straight (Stanford) have also identified Plk1 as a key regulator of cleavage furrow formation in mammalian cells.
• What Makes an Osteoclast Special?
  - dev cell 20(5):e2 (2011)
  A paper published in Developmental Cell that I have continuously enjoyed over the years is "Induction and Activation of the Transcription Factor NFATc1 Integrate RANKL Signaling in Terminal Differentiation of Osteoclasts" by Takayanagi et al. I like this paper for many reasons. The first one is that it asks without preconceived idea a simple question: why the osteoclast differentiation factor RANKL, and not IL-1, triggers osteoclast differentiation, because both cytokines affect seemingly the same signaling cascade and transcription factors NF-KB and c-FOS. The approach was simple: a microarray of bone marrow stromal cells treated or not with RANKL or IL-1 to induce osteoclast differentiation. This analysis identified NFATc1, which the authors showed is the target of both c-FOS and NF-KB in osteoclasts. The authors checked all the boxes that need to be checked for a transcription factor determining cell differentiation, and more. Indeed, they identified calcium sig! naling as an activator of NFATc1, as well as genes whose expression is regulated by both c-FOS and NFATc1. This paper is beautifully written, the question posed is important, the experiments are of superb quality, and the advance for the field is highly significant. I always thought it was one of the better papers published in Developmental Cell pertaining to skeleton development. This PaperPick refers to "Induction and Activation of the Transcription Factor NFATc1 (NFAT2) Integrate RANKL Signaling in Terminal Differentiation of Osteoclasts," by H. Takayanagi, S. Kim, T. Koga, H. Nishina, M. Isshiki, H. Yoshida, A. Saiura, M. Isobe, T. Yokochi, J.-i. Inoue, E.F. Wagner, T.W. Mak, T. Kodama, and T. Taniguchi, published in December 2002. Video Abstract (112822 K) The first author of the original paper, Hiroshi Takayanagi, discusses how he decided at the time to investigate the transcriptional effectors of osteoclast RANKL signaling, within Tadatsugu Taniguchi's group.
• A Sticky Wicket: Opposing Functions of p120-Catenin in Development and Cancer
  - dev cell 20(5):e3 (2011)
  It has been known for some time that cell-cell adhesion mediated by E-cadherin and catenins is important for development and cancer in epithelial tissues. Although β-catenin is upregulated in many cancers, p120-catenin is downregulated in most human cancers. Before this study, the molecular mechanism underlying β-catenin function in tumorigenesis was well on its way to being worked out, but little was known about p120. This paper piqued my interest because it showed that p120 was a major regulator of E-cadherin stability in the salivary gland. Its loss caused a major decrease in E-cadherin with severe defects in cell-cell adhesion and tissue morphology resembling intraepithelial hyperplasia. I liked this paper because it made me think about how looking at development gives important insights into cancer and about how two related molecules that bind to E-cadherin could behave in opposite ways to get the initial phases of tumorigenesis started. This PaperPick refers to "Blocked Acinar Development, E-Cadherin Reduction, and Intraepithelial Neoplasia upon Ablation of p120-Catenin in the Mouse Salivary Gland," by M.A. Davis and A.B. Reynolds, published in January 2006. Video Abstract (54216 K) Albert Reynolds discusses how his group came to examine the role of p120-catenin in the mouse salivary gland and the implications of their findings.
• Parsing p53 Transactivation
  - dev cell 20(5):573-574 (2011)
  Two functions of p53 are undisputed. Biologically, p53 is a potent tumor suppressor, whereas biochemically, it is a robust transcriptional activator of numerous target genes. Are these biological and biochemical functions of p53 related? The surprising answer, recently reported by Brady et al. (2011) in Cell, is minimally.
• There Is More to Life than Death: A Moonlighting Function of a Bcl-2 Member
  - dev cell 20(5):575-576 (2011)
  Members of the Bcl-2 family proteins are best known for their roles in apoptosis regulation. In this issue of Developmental Cell, Popgeorgiev et al. (2011) have uncovered a new, nonapoptotic role for a Bcl-2 homolog during early embryogenesis in zebrafish.
• Fine-Tuning Endothelial Notch: SIRT-ainly an Unexpected Mechanism
  - dev cell 20(5):577-578 (2011)
  Guarani et al. (2011), reporting in Nature, identify a mechanism for fine-tuning endothelial Notch signaling by SIRT1-mediated deacetylation. This regulation is critical for vascular sprouting and raises intriguing questions about therapeutic targeting of SIRT1 in angiogenesis and the potential mechanisms that link vascular growth and energy homeostasis.
• Coordinating Migratory Neuron Polarization by Numb-ing Communication
  - dev cell 20(5):578-580 (2011)
  An interplay between intrinsic polarity and extracellular cues guides neuronal migration during cerebellar development. In this issue of Developmental Cell, Zhou et al. (2011) demonstrate that Numb is the focal point in mediating the chemotactic response of migrating cerebellar granule cells to BDNF through its regulation of cell polarity.
• The Curious Case of the Soluble Protein
  - dev cell 20(5):581-582 (2011)
  How neurons tackle the challenge of soluble protein delivery to the distal axon has long puzzled neuroscientists. Reporting in Neuron, Scott et al. (2011) show that this axonal transport occurs through motor-dependent formation of dynamic heterogeneous protein complexes that pause upon complex disassembly and regain motility upon reassembly.
• The WTX Tumor Suppressor Regulates Mesenchymal Progenitor Cell Fate Specification
  - dev cell 20(5):583-596 (2011)
  WTX is an X-linked tumor suppressor targeted by somatic mutations in Wilms tumor, a pediatric kidney cancer, and by germline inactivation in osteopathia striata with cranial sclerosis, a bone overgrowth syndrome. Here, we show that Wtx deletion in mice causes neonatal lethality, somatic overgrowth, and malformation of multiple mesenchyme-derived tissues, including bone, fat, kidney, heart, and spleen. Inactivation of Wtx at different developmental stages and in primary mesenchymal progenitor cells (MPCs) reveals that bone mass increase and adipose tissue deficiency are due to altered lineage fate decisions coupled with delayed terminal differentiation. Specification defects in MPCs result from aberrant β-catenin activation, whereas alternative pathways contribute to the subsequently delayed differentiation of lineage-restricted cells. Thus, Wtx is a regulator of MPC commitment and differentiation with stage-specific functions in inhibiting canonical Wnt signaling. Fur! thermore, the constellation of anomalies in Wtx null mice suggests that this tumor suppressor broadly regulates MPCs in multiple tissues.
• Genome-wide Analysis of Simultaneous GATA1/2, RUNX1, FLI1, and SCL Binding in Megakaryocytes Identifies Hematopoietic Regulators
  - dev cell 20(5):597-609 (2011)
  Hematopoietic differentiation critically depends on combinations of transcriptional regulators controlling the development of individual lineages. Here, we report the genome-wide binding sites for the five key hematopoietic transcription factors—GATA1, GATA2, RUNX1, FLI1, and TAL1/SCL—in primary human megakaryocytes. Statistical analysis of the 17,263 regions bound by at least one factor demonstrated that simultaneous binding by all five factors was the most enriched pattern and often occurred near known hematopoietic regulators. Eight genes not previously appreciated to function in hematopoiesis that were bound by all five factors were shown to be essential for thrombocyte and/or erythroid development in zebrafish. Moreover, one of these genes encoding the PDZK1IP1 protein shared transcriptional enhancer elements with the blood stem cell regulator TAL1/SCL. Multifactor ChIP-Seq analysis in primary human cells coupled with a high-throughput in vivo perturbation scr! een therefore offers a powerful strategy to identify essential regulators of complex mammalian differentiation processes.
• Numb Links Extracellular Cues to Intracellular Polarity Machinery to Promote Chemotaxis
  - dev cell 20(5):610-622 (2011)
  Cell polarization is essential throughout development for proliferation, migration, and differentiation. However, it is not known how extracellular cues correctly orient cell polarity at distinct stages of development. Here, we show that the endocytic adaptor protein Numb, previously characterized for its role in cell proliferation, subsequently plays an important role in cell migration. In neural precursors stimulated with the chemotactic factor BDNF, Numb binds to activated TrkB, the BDNF receptor, and functions both as an endocytic regulator for TrkB and as a scaffold for aPKC (aPKC). Thus, Numb promotes BDNF-dependent aPKC activation. Interestingly, Numb is also a substrate of aPKC. When phosphorylated, Numb exhibits increased efficacy in binding TrkB and in promoting a chemotactic response to BDNF. Therefore, Numb functions in a feed-forward loop to promote chemotaxis of neural precursors, linking BDNF, an extracellular cue, to aPKC, a critical component of the in! trinsic polarity machinery.
• Competition between Blown Fuse and WASP for WIP Binding Regulates the Dynamics of WASP-Dependent Actin Polymerization In Vivo
  - dev cell 20(5):623-638 (2011)
  Dynamic rearrangements of the actin cytoskeleton play a key role in numerous cellular processes. In Drosophila, fusion between a muscle founder cell and a fusion competent myoblast (FCM) is mediated by an invasive, F-actin-enriched podosome-like structure (PLS). Here, we show that the dynamics of the PLS is controlled by Blown fuse (Blow), a cytoplasmic protein required for myoblast fusion but whose molecular function has been elusive. We demonstrate that Blow is an FCM-specific protein that colocalizes with WASP, WIP/Solitary, and the actin focus within the PLS. Biochemically, Blow modulates the stability of the WASP-WIP complex by competing with WASP for WIP binding, leading to a rapid exchange of WASP, WIP and G-actin within the PLS, which, in turn, actively invades the adjacent founder cell to promote fusion pore formation. These studies identify a regulatory protein that modulates the actin cytoskeletal dynamics by controlling the stability of the WASP-WIP complex.
• Regulated Offloading of Cytoplasmic Dynein from Microtubule Plus Ends to the Cortex
  - dev cell 20(5):639-651 (2011)
  Cytoplasmic dynein mediates spindle orientation from the cell cortex through interactions with astral microtubules, but neither the mechanism governing its cortical targeting nor the regulation thereof is well understood. Here we show that yeast dynein offloads from microtubule plus ends to the daughter cell cortex. Mutants with an engineered peptide inserted between the tail domain and the motor head retain wild-type motor activity but exhibit enhanced offloading and cortical targeting. Conversely, shortening the "neck" sequence between the tail and motor domains precludes offloading from the microtubule plus ends. Furthermore, chimeric mutants with mammalian dynein "neck" sequences rescue targeting and function. These findings provide direct support for an active microtubule-mediated delivery process that appears to be regulated by a conserved masking/unmasking mechanism.
• ADF/Cofilin Regulates Secretory Cargo Sorting at the TGN via the Ca2+ ATPase SPCA1
  - dev cell 20(5):652-662 (2011)
  Actin-severing proteins ADF/cofilin are required for the sorting of secretory cargo at the trans-Golgi network (TGN) in mammalian cells. How do these cytoplasmic proteins interact with the cargoes in the lumen of the TGN? Put simply, how are these two sets of proteins connected across the TGN membrane? Mass spectrometry of cofilin1 immunoprecipitated from HeLa cells revealed the presence of actin and the Ca2+ ATPase SPCA1. Moreover, cofilin1 was localized to the TGN and bound to SPCA1 via dynamic actin. SPCA1 knockdown, like ADF/cofilin1 knockdown, inhibited Ca2+ uptake into the TGN and caused missorting of secretory cargo. These defects were rescued by the overexpression of the TGN-localized SPCA1. We propose that ADF/cofilin-dependent severing of actin filaments exposes and promotes the activation of SPCA1, which pumps Ca2+ into the lumen of the TGN for the sorting of the class of secretory cargo that binds Ca2+.
• The Apoptotic Regulator Nrz Controls Cytoskeletal Dynamics via the Regulation of Ca2+ Trafficking in the Zebrafish Blastula
  - dev cell 20(5):663-676 (2011)
  Bcl-2 family members are key regulators of apoptosis. Their involvement in other cellular processes has been so far overlooked. We have studied the role of the Bcl-2 homolog Nrz in the developing zebrafish. Nrz was found to be localized to the yolk syncytial layer, a region containing numerous mitochondria and ER membranes. Nrz knockdown resulted in developmental arrest before gastrulation, due to free Ca2+ increase in the yolk cell, activating myosin light chain kinase, which led to premature contraction of actin-myosin cables in the margin and separation of the blastomeres from the yolk cell. In the yolk syncytial layer, Nrz appears to prevent the release of Ca2+ from the endoplasmic reticulum by directly interacting with the IP3R1 Ca2+ channel. Thus, the Bcl-2 family may participate in early development, not only by controlling apoptosis but also by acting on cytoskeletal dynamics and cell movements via Ca2+ fluxes inside the embryo.
• MPK-1 ERK Controls Membrane Organization in C. elegans Oogenesis via a Sex-Determination Module
  - dev cell 20(5):677-688 (2011)
  Tissues that generate specialized cell types in a production line must coordinate developmental mechanisms with physiological demand, although how this occurs is largely unknown. In the Caenorhabditis elegans hermaphrodite, the developmental sex-determination cascade specifies gamete sex in the distal germline, while physiological sperm signaling activates MPK-1/ERK in the proximal germline to control plasma membrane biogenesis and organization during oogenesis. We discovered repeated utilization of a self-contained negative regulatory module, consisting of NOS-3 translational repressor, FEM-CUL-2 (E3 ubiquitin ligase), and TRA-1 (Gli transcriptional repressor), which acts both in sex determination and in physiological demand control of oogenesis, coordinating these processes. In the distal germline, where MPK-1 is not activated, TRA-1 represses the male fate as NOS-3 functions in translational repression leading to inactivation of the FEM-CUL-2 ubiquitin ligase. In th! e proximal germline, sperm-dependent physiological MPK-1 activation results in phosphorylation-based inactivation of NOS-3, FEM-CUL-2-mediated degradation of TRA-1 and the promotion of membrane organization during oogenesis.
• β-Catenin-Dependent FGF Signaling Sustains Cell Survival in the Anterior Embryonic Head by Countering Smad4
  - dev cell 20(5):689-699 (2011)
  Growing evidence suggests that FGFs secreted from embryonic signaling centers are key mediators of cell survival. However, the mechanisms regulating FGF-dependent cell survival remain obscure. At the rostral end of the embryo, for example, ablation of FGF signaling leads to the rapid death of the precursor cells that form the anterior head, including the telencephalon. Here, we outline a core genetic circuit that regulates survival in the embryonic mouse head: WNT signaling through β-catenin directly maintains FGF expression and requires FGF function in vivo to oppose proapoptotic TGF-β signaling through SMAD4. Moreover, these antagonistic pathways converge on the transcriptional regulation of apoptosis, and genes such as Cdkn1a, suggesting a mechanism for how signaling centers in the embryonic head regulate cell survival.
• A Screen for Conditional Growth Suppressor Genes Identifies the Drosophila Homolog of HD-PTP as a Regulator of the Oncoprotein Yorkie
  - dev cell 20(5):700-712 (2011)
  Mammalian cancers depend on "multiple hits," some of which promote growth and some of which block apoptosis. We screened for mutations that require a synergistic block in apoptosis to promote tissue overgrowth and identified myopic (mop), the Drosophila homolog of the candidate tumor-suppressor and endosomal regulator His-domain protein tyrosine phosphatase (HD-PTP). We find that Myopic regulates the Salvador/Warts/Hippo (SWH) tumor suppressor pathway: Myopic PPxY motifs bind conserved residues in the WW domains of the transcriptional coactivator Yorkie, and Myopic colocalizes with Yorkie at endosomes. Myopic controls Yorkie endosomal association and protein levels, ultimately influencing expression of some Yorkie target genes. However, the antiapoptotic gene diap1 is not affected, which may explain the conditional nature of the myopic growth phenotype. These data establish Myopic as a Yorkie regulator and implicate Myopic-dependent association of Yorkie with endos! omal compartments as a regulatory step in nuclear outputs of the SWH pathway.
• Bone Regenerates via Dedifferentiation of Osteoblasts in the Zebrafish Fin
  - dev cell 20(5):713-724 (2011)
  While mammals have a limited capacity to repair bone defects, zebrafish can completely regenerate amputated bony structures of their fins. Fin regeneration is dependent on formation of a blastema, a progenitor cell pool accumulating at the amputation plane. It is unclear which cells the blastema is derived from, whether it forms by dedifferentiation of mature cells, and whether blastema cells are multipotent. We show that mature osteoblasts dedifferentiate and form part of the blastema. Osteoblasts downregulate expression of intermediate and late bone differentiation markers and induce genes expressed by bone progenitors. Dedifferentiated osteoblasts proliferate in a FGF-dependent manner and migrate to form part of the blastema. Genetic fate mapping shows that osteoblasts only give rise to osteoblasts in the regenerate, indicating that dedifferentiation is not associated with the attainment of multipotency. Thus, bone can regenerate from mature osteoblasts via dediffer! entiation, a finding with potential implications for human bone repair.
• Fate Restriction in the Growing and Regenerating Zebrafish Fin
  - dev cell 20(5):725-732 (2011)
  We use transposon-based clonal analysis to identify the lineage classes that make the adult zebrafish caudal fin. We identify nine distinct lineage classes, including epidermis, melanocyte/xanthophore, iridophore, intraray glia, lateral line, osteoblast, dermal fibroblast, vascular endothelium, and resident blood. These lineage classes argue for distinct progenitors, or organ founding stem cells (FSCs), for each lineage, which retain fate restriction throughout growth of the fin. Thus, distinct FSCs exist for the four neuroectoderm lineages, and dermal fibroblasts are not progenitors for fin ray osteoblasts; however, artery and vein cells derive from a shared lineage in the fin. Transdifferentiation of cells or lineages in the regeneration blastema is often postulated. However, our studies of single progenitors or FSCs reveal no transfating or transdifferentiation between these lineages in the regenerating fin. This result shows that, the same as in growth, lineages re! tain fate restriction when passed through the regeneration blastema.