Hot off the presses! Mar 15 dev cell

The Mar 15 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:

• Lack of Smad or Notch Leads to a Fatal Game of Brain Pericyte Hopscotch
  - dev cell 20(3):279-280 (2011)
  Pericytes surround and stabilize the vast capillary network of the central nervous system. In this issue of Developmental Cell, Li et al. (2011) show that Smad4 and Notch signaling together regulate endothelial expression of an adhesion factor, N-cadherin, which couples pericytes to the endothelial cell wall, thereby preventing neonatal intraventricular hemorrhage.
• Mitotic Phosphorylation of Nucleoporins: Dismantling NPCs and Beyond
  - dev cell 20(3):281-282 (2011)
  Recently reporting in Cell, Laurell et al. (2011) demonstrate that the hyperphosphorylation of vertebrate Nup98 by distinct mitotic kinases contributes to its release from nuclear pores, drives nuclear envelope permeabilization, and may provide a molecular switch coordinating nuclear envelope breakdown and spindle formation.
• FORMIN Stable Kinetochore-Microtubule Attachments
  - dev cell 20(3):283-284 (2011)
  Formins are well-known for promoting actin assembly, but they also play a lesser-studied role in microtubule stabilization. In this issue of Developmental Cell, Cheng et al. (2011) demonstrate that the formin homology protein mDia3 is regulated by Aurora B Kinase and contributes to the generation of kinetochore-microtubule attachments in mitosis.
• The Ins and Outs of Heterochromatic DNA Repair
  - dev cell 20(3):285-287 (2011)
  Repetitive DNA is often packaged into heterochromatin structures that prevent illicit recombination events that cause genomic instability. A recent study by Chiolo et al. (2011) published in Cell finds that DNA double-strand breaks formed within heterochromatin are shuttled to adjacent sites that are "safe" to complete repair by recombination.
• piRNAs Meet Mitochondria
  - dev cell 20(3):287-288 (2011)
  zuc/MitoPLD encodes a conserved enzyme that localizes to mitochondria and hydrolyzes the mitochondria-specific lipid cardiolipin. Surprisingly, zuc/MitoPLD activity is required for Piwi-interacting RNA (piRNA)-mediated silencing of transposable elements in fly and mouse germlines, suggesting that signaling from mitochondria influences the piRNA pathway.
• Stopped in Translation: EMT Control Meets Eukaryotic Elongation
  - dev cell 20(3):289-290 (2011)
  Recently reporting in Molecular Cell, Hussey et al. (2011) find that hnRNP E1 inhibits the translation of several genes essential for the epithelial-to-mesenchymal transition (EMT) by blocking eEF1A1 release during translation elongation. Phosphorylation of hnRNP E1 in response to TGF-β signaling disrupts the hnRNP E1-eEF1A1 interaction, triggering EMT.
• Endothelial Smad4 Maintains Cerebrovascular Integrity by Activating N-Cadherin through Cooperation with Notch
  - dev cell 20(3):291-302 (2011)
  Cerebrovascular dysfunction is strongly associated with neonatal intracranial hemorrhage (ICH) and stroke in adults. Cerebrovascular endothelial cells (ECs) play important roles in maintaining a stable cerebral circulation in the central nervous system by interacting with pericytes. However, the genetic mechanisms controlling the functions of cerebral ECs are still largely unknown. Here, we report that disruption of Smad4, the central intracellular mediator of transforming growth factor-β (TGF-β) signaling, specifically in the cerebral ECs, results in perinatal ICH and blood-brain barrier breakdown. Furthermore, the mutant vessels exhibit defective mural cell coverage. Smad4 stabilizes cerebrovascular EC-pericyte interactions by regulating the transcription of N-cadherin through associating with the Notch intracellular complex at the RBP-J binding site of the N-cadherin promoter. These findings uncover a distinct role of endothelial Smad4 in maintaining cerebrovascul! ar integrity and suggest important implications for genetic or functional deficiencies in TGF-β/Smad signaling in the pathogenesis of cerebrovascular dysfunction.
• Rspo3 Binds Syndecan 4 and Induces Wnt/PCP Signaling via Clathrin-Mediated Endocytosis to Promote Morphogenesis
  - dev cell 20(3):303-314 (2011)
  The R-Spondin (Rspo) family of secreted Wnt modulators is involved in development and disease and holds therapeutic promise as stem cell growth factors. Despite growing biological importance, their mechanism of action is poorly understood. Here, we show that Rspo3 binds syndecan 4 (Sdc4) and that together they activate Wnt/PCP signaling. In Xenopus embryos, Sdc4 and Rspo3 are essential for two Wnt/PCP-driven processes—gastrulation movements and head cartilage morphogenesis. Rspo3/PCP signaling during gastrulation requires Wnt5a and is transduced via Fz7, Dvl, and JNK. Rspo3 functions by inducing Sdc4-dependent, clathrin-mediated endocytosis. We show that this internalization is essential for PCP signal transduction, suggesting that endocytosis of Wnt-receptor complexes is a key mechanism by which R-spondins promote Wnt signaling.
• Elimination of Oncogenic Neighbors by JNK-Mediated Engulfment in Drosophila
  - dev cell 20(3):315-328 (2011)
  A newly emerged oncogenic cell in the epithelial population has to confront antitumor selective pressures in the host tissue. However, the mechanisms by which surrounding normal tissue exerts antitumor effects against oncogenically transformed cells are poorly understood. In Drosophila imaginal epithelia, clones of cells mutant for evolutionarily conserved tumor suppressor genes such as scrib or dlg lose their epithelial integrity and are eliminated from epithelia when surrounded by wild-type tissue. Here, we show that surrounding normal cells activate nonapoptotic JNK signaling in response to the emergence of oncogenic mutant cells. This JNK activation leads to upregulation of PVR, the Drosophila PDGF/VEGF receptor. Genetic and time-lapse imaging analyses reveal that PVR expression in surrounding cells activates the ELMO/Mbc-mediated phagocytic pathway, thereby eliminating oncogenic neighbors by engulfment. Our data indicate that JNK-mediated cell engulfment could be ! an evolutionarily conserved intrinsic tumor-suppression mechanism that eliminates premalignant cells from epithelia.
• A Dynamic Complex of Signaling Proteins Uses Polar Localization to Regulate Cell-Fate Asymmetry in Caulobacter crescentus
  - dev cell 20(3):329-341 (2011)
  Cellular asymmetry is critical to metazoan development and the life cycle of many microbes. In Caulobacter, cell cycle progression and the formation of asymmetric daughter cells depend on the polarly-localized histidine kinase CckA. How CckA is regulated and why activity depends on localization are unknown. Here, we demonstrate that the unorthodox kinase DivL promotes CckA activity and that the phosphorylated regulator DivK inhibits CckA by binding to DivL. Early in the cell cycle, CckA is activated by the dephosphorylation of DivK throughout the cell. However, in later stages, when phosphorylated DivK levels are high, CckA activation relies on polar localization with a DivK phosphatase. Localization thus creates a protected zone for CckA within the cell, without the use of membrane-enclosed compartments. Our results reveal the mechanisms by which CckA is regulated in a cell-type-dependent manner. More generally, our findings reveal how cells exploit subcellular locali! zation to orchestrate sophisticated regulatory processes.
• Aurora B Regulates Formin mDia3 in Achieving Metaphase Chromosome Alignment
  - dev cell 20(3):342-352 (2011)
  Proper bipolar attachment of sister kinetochores to the mitotic spindle is critical for accurate chromosome segregation in mitosis. Here we show an essential role of the formin mDia3 in achieving metaphase chromosome alignment. This function is independent of mDia3 actin nucleation activity, but is attributable to EB1-binding by mDia3. Furthermore, the microtubule binding FH2 domain of mDia3 is phosphorylated by Aurora B kinase in vitro, and cells expressing the nonphosphorylatable mDia3 mutant cannot position chromosomes at the metaphase plate. Purified recombinant mDia3 phosphorylated by Aurora B exhibits reduced ability to bind microtubules and stabilize microtubules against cold-induced disassembly in vitro. Cells expressing the phosphomimetic mDia3 mutant do not form stable kinetochore microtubule fibers; despite they are able to congress chromosomes to the metaphase plate. These findings reveal a key role for mDia3 and its regulation by Aurora B phosphorylation i! n achieving proper stable kinetochore microtubule attachment.
• DNA Damage during Meiosis Induces Chromatin Remodeling and Synaptonemal Complex Disassembly
  - dev cell 20(3):353-363 (2011)
  DNA damage to the germline genome must be accurately repaired to ensure transmission of intact genetic information to following generations. Meiosis presents challenges to the DNA damage response (DDR) because it universally requires changes to chromosome structure that can affect DNA repair outcomes. We report the existence of a meiotic DDR at chromosome axes that results in chromatin remodeling, synaptonemal complex disassembly, and axis separation in response to irradiation at late pachytene stages in C. elegans. The axis component HTP-3 is required for germline acquisition of H2AacK5, an axis-specific chromatin mark that is DNA damage responsive. Irradiated wild-types show reduction of H2AacK5 and axis separation that are dependent on the acetyltransferase MYS-1/TIP60. Restoration of H2AacK5 levels requires ATM-1 kinase and correlates with resynapsis. We propose that the meiotic DDR involves early chromatin remodeling at chromosome axes to dismantle structures prom! oting interhomolog recombination and facilitate efficient nonhomolog-based repair before pachytene exit.
• MITOPLD Is a Mitochondrial Protein Essential for Nuage Formation and piRNA Biogenesis in the Mouse Germline
  - dev cell 20(3):364-375 (2011)
  MITOPLD is a member of the phospholipase D superfamily proteins conserved among diverse species. Zucchini (Zuc), the Drosophila homolog of MITOPLD, has been implicated in primary biogenesis of Piwi-interacting RNAs (piRNAs). By contrast, MITOPLD has been shown to hydrolyze cardiolipin in the outer membrane of mitochondria to generate phosphatidic acid, which is a signaling molecule. To assess whether the mammalian MITOPLD is involved in piRNA biogenesis, we generated Mitopld mutant mice. The mice display meiotic arrest during spermatogenesis, demethylation and derepression of retrotransposons, and defects in primary piRNA biogenesis. Furthermore, in mutant germ cells, mitochondria and the components of the nuage, a perinuclear structure involved in piRNA biogenesis/function, are mislocalized to regions around the centrosome, suggesting that MITOPLD may be involved in microtubule-dependent localization of mitochondria and these proteins. Our results indicate a conserved! role for MITOPLD/Zuc in the piRNA pathway and link mitochondrial membrane metabolism/signaling to small RNA biogenesis.
• piRNA-Associated Germline Nuage Formation and Spermatogenesis Require MitoPLD Profusogenic Mitochondrial-Surface Lipid Signaling
  - dev cell 20(3):376-387 (2011)
  The mammalian Phospholipase D MitoPLD facilitates mitochondrial fusion by generating the signaling lipid phosphatidic acid (PA). The Drosophila MitoPLD homolog Zucchini (Zuc), a proposed cytoplasmic nuclease, is required for piRNA generation, a critical event in germline development. We show that Zuc localizes to mitochondria and has MitoPLD-like activity. Conversely, MitoPLD−/− mice exhibit the meiotic arrest, DNA damage, and male sterility characteristic of mice lacking piRNAs. The primary function of MitoPLD seems to be the generation of mitochondrial-surface PA. This PA in turn recruits the phosphatase Lipin 1, which converts PA to diacylglycerol and promotes mitochondrial fission, suggesting a mechanism for mitochondrial morphology homeostasis. MitoPLD and Lipin 1 have opposing effects on mitochondria length and on intermitochondrial cement (nuage), a structure found between aggregated mitochondria that is implicated in piRNA generation. We propose that mitoch! ondrial-surface PA generated by MitoPLD/Zuc recruits or activates nuage components critical for piRNA production.
• Target-Mediated Protection of Endogenous MicroRNAs in C. elegans
  - dev cell 20(3):388-396 (2011)
  MicroRNAs (miRNAs) are tightly regulated through transcriptional and posttranscriptional mechanisms, including degradation by nucleases. Here, we report that in C. elegans, target mRNAs can protect their cognate miRNAs from degradation in vivo. We show that the let-7(n2853) mutation destabilizes the mature let-7 miRNA by impairing this protection. Moreover, presence of a cognate target or depletion of the xrn-1 (XRN1) or xrn-2 (XRN2/Rat1p) exoribonucleases enforces accumulation of certain miRNA passenger (miR*) strands. Thus, following biased miRNA strand loading into Argonaute, elimination of nonfunctional RNAs can further refine miRNA strand selection. Conversely, by aligning the levels of miRNAs with those of their targets, the opposing activities of mature miRNA degradation and target-mediated miRNA protection (TMMP) may enable dynamic expression of either mature strand of a pre-miRNA, and evolution of miRNAs. Thus, it seems that mRNAs are more than inert targets a! nd function with miRNAs in a network of mutual regulation.
• Retinoic Acid Production by Endocardium and Epicardium Is an Injury Response Essential for Zebrafish Heart Regeneration
  - dev cell 20(3):397-404 (2011)
  Zebrafish heart regeneration occurs through the activation of cardiomyocyte proliferation in areas of trauma. Here, we show that within 3 hr of ventricular injury, the entire endocardium undergoes morphological changes and induces expression of the retinoic acid (RA)-synthesizing enzyme raldh2. By one day posttrauma, raldh2 expression becomes localized to endocardial cells at the injury site, an area that is supplemented with raldh2-expressing epicardial cells as cardiogenesis begins. Induced transgenic inhibition of RA receptors or expression of an RA-degrading enzyme blocked regenerative cardiomyocyte proliferation. Injured hearts of the ancient fish Polypterus senegalus also induced and maintained robust endocardial and epicardial raldh2 expression coincident with cardiomyocyte proliferation, whereas poorly regenerative infarcted murine hearts did not. Our findings reveal that the endocardium is a dynamic, injury-responsive source of RA in zebrafish, and indicate ke! y roles for endocardial and epicardial cells in targeting RA synthesis to damaged heart tissue and promoting cardiomyocyte proliferation.
• Microautophagy of Cytosolic Proteins by Late Endosomes
  - dev cell 20(3):405-406 (2011)
  
• Vangl2 Promotes Wnt/Planar Cell Polarity-like Signaling by Antagonizing Dvl1-Mediated Feedback Inhibition in Growth Cone Guidance
  - dev cell 20(3):407 (2011)
  
• Transcriptional Activation of Arabidopsis Axis Patterning Genes WOX8/9 Links Zygote Polarity to Embryo Development
  - dev cell 20(3):408 (2011)