Hot off the presses! Oct 19 dev cell

The Oct 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:

• Linc-ing Long Noncoding RNAs and Enhancer Function
  - dev cell 19(4):485-486 (2010)
  Enhancers are distal regulatory sequences that control gene expression in development. Ørom et al. now report inCell that some long noncoding RNAs have functional properties of enhancers. Known enhancers are also transcribed in cells in which they are active, suggesting that noncoding RNAs are integral to enhancer action.
• How the Sea Squirt Nucleus Tells Mesoderm Not to Be Endoderm
  - dev cell 19(4):487-488 (2010)
  Sea squirts are simple invertebrate chordates. In this issue of Developmental Cell, Takatori et al. show nuclear migration within ascidian mesendodermal cells enables polarized localization of Not mRNA, which encodes a homeobox protein that distinguishes mesoderm from endoderm fates. The link between nuclear migration and mRNA localization suggests exciting parallels with protostomes.
• Stem Cell Fate in Proliferating Tissues: Equal Odds in a Game of Chance
  - dev cell 19(4):489-490 (2010)
  Quantitative lineage tracing reveals stem cell fate in vivo. A new study in a recent issue of Cell shows intestinal crypt stem cells are functionally equivalent, with equal odds of differentiation. Differentiating stem cells are replaced by the symmetric division of adjacent stem cells.
• The Hippo Signaling Pathway in Development and Cancer
  - dev cell 19(4):491-505 (2010)
  First discovered in Drosophila, the Hippo signaling pathway is a conserved regulator of organ size. Central to this pathway is a kinase cascade leading from the tumor suppressor Hippo (Mst1 and Mst2 in mammals) to the oncoprotein Yki (YAP and TAZ in mammals), a transcriptional coactivator of target genes involved in cell proliferation and survival. Here, I review recent progress in elucidating the molecular mechanism and physiological function of Hippo signaling in Drosophila and mammals. These studies suggest that the core Hippo kinase cascade integrates multiple upstream inputs, enabling dynamic regulation of tissue homeostasis in animal development and physiology.
• Evidence for a Growth-Stabilizing Regulatory Feedback Mechanism between Myc and Yorkie, the Drosophila Homolog of Yap
  - dev cell 19(4):507-520 (2010)
  An understanding of how animal size is controlled requires knowledge of how positive and negative growth regulatory signals are balanced and integrated within cells. Here we demonstrate that the activities of the conserved growth-promoting transcription factor Myc and the tumor-suppressing Hippo pathway are codependent during growth of Drosophila imaginal discs. We find that Yorkie (Yki), the Drosophila homolog of the Hippo pathway transducer, Yap, regulates the transcription of Myc, and that Myc functions as a critical cellular growth effector of the pathway. We demonstrate that in turn, Myc regulates the expression of Yki as a function of its own cellular level, such that high levels of Myc repress Yki expression through both transcriptional and posttranscriptional mechanisms. We propose that the codependent regulatory relationship functionally coordinates the cellular activities of Yki and Myc and provides a mechanism of growth control that regulates organ size and ! has broad implications for cancer.
• Regulation of TCF3 by Wnt-Dependent Phosphorylation during Vertebrate Axis Specification
  - dev cell 19(4):521-532 (2010)
  A commonly accepted model of Wnt/β-catenin signaling involves target gene activation by a complex of β-catenin with a T-cell factor (TCF) family member. TCF3 is a transcriptional repressor that has been implicated in Wnt signaling and plays key roles in embryonic axis specification and stem cell differentiation. Here we demonstrate that Wnt proteins stimulate TCF3 phosphorylation in gastrulating Xenopus embryos and mammalian cells. This phosphorylation event involves β-catenin-mediated recruitment of homeodomain-interacting protein kinase 2 (HIPK2) to TCF3 and culminates in the dissociation of TCF3 from a target gene promoter. Mutated TCF3 proteins resistant to Wnt-dependent phosphorylation function as constitutive inhibitors of Wnt-mediated activation of Vent2 and Cdx4 during anteroposterior axis specification. These findings reveal an alternative in vivo mechanism of Wnt signaling that involves TCF3 phosphorylation and subsequent derepression of target genes and l! ink this molecular event to a specific developmental process.
• Zfp521 Is a Target Gene and Key Effector of Parathyroid Hormone-Related Peptide Signaling in Growth Plate Chondrocytes
  - dev cell 19(4):533-546 (2010)
  In the growth plate, the interplay between parathyroid hormone-related peptide (PTHrP) and Indian hedgehog (Ihh) signaling tightly regulates chondrocyte proliferation and differentiation during longitudinal bone growth. We found that PTHrP increases the expression of Zfp521, a zinc finger transcriptional coregulator, in prehypertrophic chondrocytes. Mice with chondrocyte-targeted deletion of Zfp521 resembled PTHrP−/− and chondrocyte-specific PTHR1−/− mice, with decreased chondrocyte proliferation, early hypertrophic transition, and reduced growth plate thickness. Deleting Zfp521 increased expression of Runx2 and Runx2 target genes, and decreased Cyclin D1 and Bcl-2 expression while increasing Caspase-3 activation and apoptosis. Zfp521 associated with Runx2 in chondrocytes, antagonizing its activity via an HDAC4-dependent mechanism. PTHrP failed to upregulate Cyclin D1 and to antagonize Runx2, Ihh, and collagen X expression when Zfp521 was absent. Thus, Zfp521 i! s an important PTHrP target gene that regulates growth plate chondrocyte proliferation and differentiation.
• Jiraiya Attenuates BMP Signaling by Interfering with Type II BMP Receptors in Neuroectodermal Patterning
  - dev cell 19(4):547-561 (2010)
  During embryogenesis, bone morphogenetic protein (BMP) signaling needs to be finely tuned in a locally restricted manner. Here, we report a cell-intrinsic mode of BMP response control executed by the membrane protein Jiraiya. In the Xenopus embryo, zygotic Jiraiya, expressed exclusively in the neuroectoderm, is essential and sufficient for limiting dorsal neural development, which is dependent on BMP signals. In animal cap assays, Jiraiya selectively and cell-autonomously inhibits BMP signaling, while Jiraiya's knockdown enhances the signaling. In the cell, Jiraiya selectively forms a complex with type II BMP receptor (BMPRII) and downregulates the cell surface localization of functional BMPRII. This functional interaction with Jiraiya depends on the unique tail domain of BMPRII, and, in particular, the conserved EVNNNG motif, the function of which has been unknown. Thus, Jiraiya represents a cell-intrinsic cutoff mechanism for dynamic responsiveness to BMP signals via! subtype-selective receptor control.
• Drosophila SPARC Is a Self-Protective Signal Expressed by Loser Cells during Cell Competition
  - dev cell 19(4):562-573 (2010)
  During development and aging, animals suffer insults that modify the fitness of individual cells. In Drosophila, the elimination of viable but suboptimal cells is mediated by cell competition, ensuring that these cells do not accumulate during development. In addition, certain genes such as the Drosophila homolog of human c-myc (dmyc) are able to transform cells into supercompetitors, which eliminate neighboring wild-type cells by apoptosis and overproliferate, leaving total cell numbers unchanged. Here we have identified Drosophila Sparc as an early marker transcriptionally upregulated in loser cells that provides a transient protection by inhibiting Caspase activation in outcompeted cells. Overall, we describe the unexpected existence of a physiological mechanism that counteracts cell competition during development.
• Integrin-Linked Kinase Controls Microtubule Dynamics Required for Plasma Membrane Targeting of Caveolae
  - dev cell 19(4):574-588 (2010)
  Caveolae are specialized compartments of the plasma membrane that are involved in signaling, endocytosis, and cholesterol transport. Their formation requires the transport of caveolin-1 to the plasma membrane, but the molecular mechanisms regulating the transport are largely unknown. Here, we identify a critical role for adhesion-mediated signaling through β1 integrins and integrin-linked kinase (ILK) in caveolae formation. Mice lacking β1 integrins or ILK in keratinocytes have dramatically reduced numbers of plasma membrane caveolae in vivo, which is due to impaired transport of caveolin-1-containing vesicles along microtubules (MT) to the plasma membrane. Mechanistically, ILK promotes the recruitment of the F-actin binding protein IQGAP1 to the cell cortex, which, in turn, cooperates with its effector mDia1 to locally stabilize MTs and to allow stable insertion of caveolae into the plasma membrane. Our results assign an important role to the integrin/ILK complex fo! r caveolar trafficking to the cell surface.
• Segregation of Germ Layer Fates by Nuclear Migration-Dependent Localization of Not mRNA
  - dev cell 19(4):589-598 (2010)
  An important step in early embryonic development is the allocation and segregation of germ layer fates into distinct embryonic regions. However, the mechanism that segregates the mesendoderm into mesoderm and endoderm fates remains largely unknown in most animals. Here, using ascidians, a primitive chordate, we show that these fates are segregated by partitioning of asymmetrically localized Not mRNA from the mesendoderm cell to its mesodermal daughter. Migration of the mesendoderm cell nucleus to the future mesoderm-forming region, release of Not mRNA from the nucleus, Wnt5α-dependent local retention of the mRNA, and subsequent repositioning of the mitotic spindle to the center of the cell are each required for the asymmetric localization and partitioning of Not mRNA. Our results show that nuclear migration plays an unexpected role in asymmetric cell divisions that segregate germ layer fates in chordate embryos.
• A Mec1- and PP4-Dependent Checkpoint Couples Centromere Pairing to Meiotic Recombination
  - dev cell 19(4):599-611 (2010)
  The faithful alignment of homologous chromosomes during meiotic prophase requires the coordination of DNA double-strand break (DSB) repair with large-scale chromosome reorganization. Here we identify the phosphatase PP4 (Pph3/Psy2) as a mediator of this process in Saccharomyces cerevisiae. In pp4 mutants, early stages of crossover repair and homology-independent pairing of centromeres are coordinately blocked. We traced the loss of centromere pairing to the persistent phosphorylation of the chromosomal protein Zip1 on serine 75. Zip1-S75 is a consensus site for the ATR-like checkpoint kinase Mec1, and centromere pairing is restored in mec1 mutants. Importantly, Zip1-S75 phosphorylation does not alter chromosome synapsis or DSB repair, indicating that Mec1 separates centromere pairing from the other functions of Zip1. The centromeric localization and persistent activity of PP4 during meiotic prophase suggest a model whereby Zip1-S75 phosphorylation dynamically destabili! zes homology-independent centromere pairing in response to recombination initiation, thereby coupling meiotic chromosome dynamics to DSB repair.
• The Mammalian Doublesex Homolog DMRT1 Is a Transcriptional Gatekeeper that Controls the Mitosis versus Meiosis Decision in Male Germ Cells
  - dev cell 19(4):612-624 (2010)
  The switch from mitosis to meiosis is a unique feature of germ cell development. In mammals, meiotic initiation requires retinoic acid (RA), which activates meiotic inducers, including Stra8, but how the switch to meiosis is controlled in male germ cells (spermatogonia) remains poorly understood. Here we examine the role of the Doublesex-related transcription factor DMRT1 in adult spermatogenesis using conditional gene targeting in the mouse. Loss of Dmrt1 causes spermatogonia to precociously exit the spermatogonial program and enter meiosis. Therefore, DMRT1 determines whether male germ cells undergo mitosis and spermatogonial differentiation or meiosis. Loss of Dmrt1 in spermatogonia also disrupts cyclical gene expression in Sertoli cells. DMRT1 acts in spermatogonia to restrict RA responsiveness, directly repress Stra8 transcription, and activate transcription of the spermatogonial differentiation factor Sohlh1, thereby preventing meiosis and promoting spermatogonia! l development. By coordinating spermatogonial development and mitotic amplification with meiosis, DMRT1 allows abundant, continuous production of sperm.
• A Strand-Specific Burst in Transcription of Pericentric Satellites Is Required for Chromocenter Formation and Early Mouse Development
  - dev cell 19(4):625-638 (2010)
  At the time of fertilization, the paternal genome lacks the typical configuration and marks characteristic of pericentric heterochromatin. It is thus essential to understand the dynamics of this region during early development, its importance during that time period and how a somatic configuration is attained. Here, we show that pericentric satellites undergo a transient peak in expression precisely at the time of chromocenter formation. This transcription is regulated in a strand-specific manner in time and space and is strongly biased by the parental asymmetry. The transcriptional upregulation follows a developmental clock, yet when replication is blocked chromocenter formation is impeded. Furthermore, interference with major satellite transcripts using locked nucleic acid (LNA)-DNA gapmers results in developmental arrest before completion of chromocenter formation. We conclude that the exquisite strand-specific expression dynamics at major satellites during the 2-ce! ll stage, with both up and downregulation, are necessary events for proper chromocenter organization and developmental progression.