Monday, November 15, 2010

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.

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