Latest Articles Include:
- Breaking the Silence: Stimulating Proliferation of Adult Cardiomyocytes
Braun T Dimmeler S - Dev Cell 17(2):151-153 (2009)
Several recent findings challenge our view of the heart as a postmitotic organ and suggest that the adult heart has some capacity to regenerate. Bersell et al. in a recent issue of Cell report that neuregulin1-mediated activation of ErbB2/4 receptors induces proliferation of adult mononuclear cardiomyocytes. - Notch Signaling: Linking Delta Endocytosis and Cell Polarity
Krahn MP Wodarz A - Dev Cell 17(2):153-154 (2009)
Activation of Notch by its transmembrane ligand Delta requires the E3 ubiquitin ligases Neuralized or Mind bomb and endocytosis of the ubiquitinated ligand. In this issue of Developmental Cell, Ossipova et al. show that the polarity regulator PAR-1 phosphorylates Mind bomb, leading to the degradation of Mind bomb and to changes in cell fate due to loss of Notch signaling. - Who's the Boss? One-Way Conversations between Bacteria
Kroos L - Dev Cell 17(2):155-156 (2009)
Bacteria communicate via extracellular signals. Most signaling studied so far has been bidirectional. A recent study shows that when Bacillus subtilis build a multicellular biofilm, some conversations are unidirectional. - Atlasin GTPases Shape Up ER Networks
Barlowe C - Dev Cell 17(2):157-158 (2009)
The endoplasmic reticulum (ER) adopts a remarkable array of flattened membrane structures and branched tubular networks to support cellular function. Recent studies reveal that the integral membrane atlastin GTPases, which are linked to neurodegenerative diseases, catalyze membrane fusion and are required for the formation of branched membrane networks characteristic of the ER. - Integrins Anchor the Invasive Machinery
Wickström SA Fässler R - Dev Cell 17(2):158-160 (2009)
Cell invasion through the basement membrane, a process important for both development and disease pathogenesis, depends on an interplay of adhesive, force transducing, proteolytic, and chemotactic machineries. The mechanisms whereby these different processes are integrated on the cellular level have remained elusive. In this issue of Developmental Cell, Sherwood and coworkers now identify integrins as integration platforms for a specialized invasive membrane domain in C. elegans. - LIN28 lets BLIMP1 Take the Right Course
Matzuk MM - Dev Cell 17(2):160-161 (2009)
The transcription factor BLIMP1 is a master regulator of primordial germ cell (PGC) specification and is suppressed by the microRNA let-7. In a recent issue of Nature, West and colleagues use a unique in vitro ES cell differentiation strategy to show that LIN28 is an essential regulator of PGC formation through inhibition of let-7 maturation and consequential induction of BLIMP1. - A Developmental Perspective: Changes in the Position of the Blastopore during Bilaterian Evolution
Martindale MQ Hejnol A - Dev Cell 17(2):162-174 (2009)
Progress in resolving the phylogenetic relationships among animals and the expansion of molecular developmental studies to a broader variety of organisms has provided important insights into the evolution of developmental programs. These new studies make it possible to reevaluate old hypotheses about the evolution of animal body plans and to elaborate new ones. Here, we review recent studies that shed light on the transition from a radially organized ancestor to the last common ancestor of the Bilateria ("Urbilaterian") and present an integrative hypothesis about plausible developmental scenarios for the evolution of complex multicellular animals. - Integrin-α9 Is Required for Fibronectin Matrix Assembly during Lymphatic Valve Morphogenesis
Bazigou E Xie S Chen C Weston A Miura N Sorokin L Adams R Muro AF Sheppard D Makinen T - Dev Cell 17(2):175-186 (2009)
Dysfunction of lymphatic valves underlies human lymphedema, yet the process of valve morphogenesis is poorly understood. Here, we show that during embryogenesis, lymphatic valve leaflet formation is initiated by upregulation of integrin-α9 expression and deposition of its ligand fibronectin-EIIIA (FN-EIIIA) in the extracellular matrix. Endothelial cell-specific deletion of Itga9 (encoding integrin-α9) in mouse embryos results in the development of rudimentary valve leaflets characterized by disorganized FN matrix, short cusps, and retrograde lymphatic flow. Similar morphological and functional defects are observed in mice lacking the EIIIA domain of FN. Mechanistically, we demonstrate that in primary human lymphatic endothelial cells, the integrin-α9-EIIIA interaction directly regulates FN fibril assembly, which is essential for the formation of the extracellular matrix core of valve leaflets. Our findings reveal an important role for integrin-α9 signaling during l! ymphatic valve morphogenesis and implicate it as a candidate gene for primary lymphedema caused by valve defects. - Integrin Acts Upstream of Netrin Signaling to Regulate Formation of the Anchor Cell's Invasive Membrane in C. elegans
Hagedorn EJ Yashiro H Ziel JW Ihara S Wang Z Sherwood DR - Dev Cell 17(2):187-198 (2009)
Integrin expression and activity have been strongly correlated with developmental and pathological processes involving cell invasion through basement membranes. The role of integrins in mediating these invasions, however, remains unclear. Utilizing the genetically and visually accessible model of anchor cell (AC) invasion in C. elegans, we have recently shown that netrin signaling orients a specialized invasive cell membrane domain toward the basement membrane. Here, we demonstrate that the integrin heterodimer INA-1/PAT-3 plays a crucial role in AC invasion, in part by targeting the netrin receptor UNC-40 (DCC) to the AC's plasma membrane. Analyses of the invasive membrane components phosphatidylinositol 4,5-bisphosphate, the Rac GTPase MIG-2, and F-actin further indicate that INA-1/PAT-3 plays a broad role in promoting the plasma membrane association of these molecules. Taken together, these studies reveal a role for integrin in regulating the plasma membrane targeti! ng and netrin-dependent orientation of a specialized invasive membrane domain. - Ret-Dependent Cell Rearrangements in the Wolffian Duct Epithelium Initiate Ureteric Bud Morphogenesis
Chi X Michos O Shakya R Riccio P Enomoto H Licht JD Asai N Takahashi M Ohgami N Kato M Mendelsohn C Costantini F - Dev Cell 17(2):199-209 (2009)
While the genetic control of renal branching morphogenesis has been extensively described, the cellular basis of this process remains obscure. GDNF/RET signaling is required for ureter and kidney development, and cells lacking Ret are excluded from the tips of the branching ureteric bud in chimeric kidneys. Here, we find that this exclusion results from earlier Ret-dependent cell rearrangements in the caudal Wolffian duct, which generate a specialized epithelial domain that later emerges as the tip of the primary ureteric bud. By juxtaposing cells with elevated or reduced RET activity, we find that Wolffian duct cells compete, based on RET signaling levels, to contribute to this domain. At the same time, the caudal Wolffian duct transiently converts from a simple to a pseudostratified epithelium, a process that does not require Ret. Thus, both Ret-dependent cell movements and Ret-independent changes in the Wolffian duct epithelium contribute to ureteric bud formation. - The N-Myc-DLL3 Cascade Is Suppressed by the Ubiquitin Ligase Huwe1 to Inhibit Proliferation and Promote Neurogenesis in the Developing Brain
Zhao X D' Arca D Lim WK Brahmachary M Carro MS Ludwig T Cardo CC Guillemot F Aldape K Califano A Iavarone A Lasorella A - Dev Cell 17(2):210-221 (2009)
Self-renewal and proliferation of neural stem cells and the decision to initiate neurogenesis are crucial events directing brain development. Here we show that the ubiquitin ligase Huwe1 operates upstream of the N-Myc-DLL3-Notch pathway to control neural stem cell activity and promote neurogenesis. Conditional inactivation of the Huwe1 gene in the mouse brain caused neonatal lethality associated with disorganization of the laminar patterning of the cortex. These defects stemmed from severe impairment of neurogenesis associated with uncontrolled expansion of the neural stem cell compartment. Loss- and gain-of-function experiments in the mouse cortex demonstrated that Huwe1 restrains proliferation and enables neuronal differentiation by suppressing the N-Myc-DLL3 cascade. Notably, human high-grade gliomas carry focal hemizygous deletions of the X-linked Huwe1 gene in association with amplification of the N-myc locus. Our results indicate that Huwe1 balances proliferation! and neurogenesis in the developing brain and that this pathway is subverted in malignant brain tumors. - PAR-1 Phosphorylates Mind Bomb to Promote Vertebrate Neurogenesis
Ossipova O Ezan J Sokol SY - Dev Cell 17(2):222-233 (2009)
Generation of neurons in the vertebrate central nervous system requires a complex transcriptional regulatory network and signaling processes in polarized neuroepithelial progenitor cells. Here we demonstrate that neurogenesis in the Xenopus neural plate in vivo and mammalian neural progenitors in vitro involves intrinsic antagonistic activities of the polarity proteins PAR-1 and aPKC. Furthermore, we show that Mind bomb (Mib), a ubiquitin ligase that promotes Notch ligand trafficking and activity, is a crucial molecular substrate for PAR-1. The phosphorylation of Mib by PAR-1 results in Mib degradation, repression of Notch signaling, and stimulation of neuronal differentiation. These observations suggest a conserved mechanism for neuronal fate determination that might operate during asymmetric divisions of polarized neural progenitor cells. - Structure and Function of the ESCRT-II-III Interface in Multivesicular Body Biogenesis
Im YJ Wollert T Boura E Hurley JH - Dev Cell 17(2):234-243 (2009)
The ESCRT-II-ESCRT-III interaction coordinates the sorting of ubiquitinated cargo with the budding and scission of intralumenal vesicles into multivesicular bodies. The interacting regions of these complexes were mapped to the second winged helix domain of human ESCRT-II subunit VPS25 and the first helix of ESCRT-III subunit VPS20. The crystal structure of this complex was determined at 2.0 Å resolution. Residues involved in structural interactions explain the specificity of ESCRT-II for Vps20, and are critical for cargo sorting in vivo. ESCRT-II directly activates ESCRT-III-driven vesicle budding and scission in vitro via these structural interactions. VPS20 and ESCRT-II bind membranes with nanomolar affinity, explaining why binding to ESCRT-II is dispensable for the recruitment of Vps20 to membranes. Docking of the ESCRT-II-VPS202 supercomplex reveals a convex membrane-binding surface, suggesting a hypothesis for negative membrane curvature induction in the nascent ! intralumenal vesicle. - Phosphorylation-Dependent Protein Interactions at the Spindle Midzone Mediate Cell Cycle Regulation of Spindle Elongation
Khmelinskii A Roostalu J Roque H Antony C Schiebel E - Dev Cell 17(2):244-256 (2009)
The metaphase-to-anaphase transition is one of the most dramatic and highly regulated steps in cell division. At anaphase onset the protease separase dissolves sister chromatid cohesion. Simultaneously, the mitotic spindle elongates as interpolar microtubules (iMTs) slide apart at the spindle midzone, ensuring chromosome segregation. However, it remains unclear how spindle elongation is coordinated with cell cycle progression. Here we demonstrate that phosphorylation of the midzone organizer Ase1 controls localization and function of Cin8, a kinesin-5 that slides iMTs relative to each other. Phosphorylation of Ase1 by Cdk1 (cyclin-dependent kinase) inhibits Cin8 binding to iMTs, preventing bending and collapse of the metaphase spindle. In anaphase Ase1 dephosphorylation by the separase-activated phosphatase Cdc14 is necessary and sufficient for Cin8 recruitment to the midzone, where it drives spindle elongation. Our results reveal that sliding forces at the midzone are! activated by separase and explain how spindle elongation is triggered with anaphase entry. - Phospho-Regulated Interaction between Kinesin-6 Klp9p and Microtubule Bundler Ase1p Promotes Spindle Elongation
Fu C Ward JJ Loiodice I Velve-Casquillas G Nedelec FJ Tran PT - Dev Cell 17(2):257-267 (2009)
The spindle midzone—composed of antiparallel microtubules, microtubule-associated proteins (MAPs), and motors—is the structure responsible for microtubule organization and sliding during anaphase B. In general, MAPs and motors stabilize the midzone and motors produce sliding. We show that fission yeast kinesin-6 motor klp9p binds to the microtubule antiparallel bundler ase1p at the midzone at anaphase B onset. This interaction depends upon the phosphorylation states of klp9p and ase1p. The cyclin-dependent kinase cdc2p phosphorylates and its antagonist phosphatase clp1p dephosphorylates klp9p and ase1p to control the position and timing of klp9p-ase1p interaction. Failure of klp9p-ase1p binding leads to decreased spindle elongation velocity. The ase1p-mediated recruitment of klp9p to the midzone accelerates pole separation, as suggested by computer simulation. Our findings indicate that a phosphorylation switch controls the spatial-temporal interactions of motors a! nd MAPs for proper anaphase B, and suggest a mechanism whereby a specific motor-MAP conformation enables efficient microtubule sliding. - The MicroRNA-Regulated SBP-Box Transcription Factor SPL3 Is a Direct Upstream Activator of LEAFY, FRUITFULL, and APETALA1
Yamaguchi A Wu MF Yang L Wu G Poethig RS Wagner D - Dev Cell 17(2):268-278 (2009)
When to form flowers is a developmental decision that profoundly impacts the fitness of flowering plants. In Arabidopsis this decision is ultimately controlled by the induction and subsequent activity of the transcription factors LEAFY (LFY), FRUITFULL (FUL), and APETALA1 (AP1). Despite their central importance, our current understanding of the regulation of LFY, FUL, and AP1 expression is still incomplete. We show here that all three genes are directly activated by the microRNA-targeted transcription factor SQUAMOSA PROMOTER BINDING PROTEIN-LIKE 3 (SPL3). Our findings suggest that SPL3 acts together with other microRNA-regulated SPL transcription factors to control the timing of flower formation. Moreover, the identified SPL activity defines a distinct pathway in control of this vital developmental decision. - Apoptotic Cells Provide an Unexpected Source of Wnt3 Signaling to Drive Hydra Head Regeneration
Chera S Ghila L Dobretz K Wenger Y Bauer C Buzgariu W Martinou JC Galliot B - Dev Cell 17(2):279-289 (2009)
Decapitated Hydra regenerate their heads via morphallaxis, i.e., without significant contributions made by cell proliferation or interstitial stem cells. Indeed, Hydra depleted of interstitial stem cells regenerate robustly, and Wnt3 from epithelial cells triggers head regeneration. However, we find a different mechanism controlling regeneration after midgastric bisection in animals equipped with both epithelial and interstitial cell lineages. In this context, we see rapid induction of apoptosis and Wnt3 secretion among interstitial cells at the head- (but not foot-) regenerating site. Apoptosis is both necessary and sufficient to induce Wnt3 production and head regeneration, even at ectopic sites. Further, we identify a zone of proliferation beneath the apoptotic zone, reminiscent of proliferative blastemas in regenerating limbs and of compensatory proliferation induced by dying cells in Drosophila imaginal discs. We propose that different types of injuries induce dis! tinct cellular modes of Hydra head regeneration, which nonetheless converge on a central effector, Wnt3. - Wnt2/2b and β-Catenin Signaling Are Necessary and Sufficient to Specify Lung Progenitors in the Foregut
Goss AM Tian Y Tsukiyama T Cohen ED Zhou D Lu MM Yamaguchi TP Morrisey EE - Dev Cell 17(2):290-298 (2009)
Patterning of the primitive foregut promotes appropriate organ specification along its anterior-posterior axis. However, the molecular pathways specifying foregut endoderm progenitors are poorly understood. We show here that Wnt2/2b signaling is required to specify lung endoderm progenitors within the anterior foregut. Embryos lacking Wnt2/2b expression exhibit complete lung agenesis and do not express Nkx2.1, the earliest marker of the lung endoderm. In contrast, other foregut endoderm-derived organs, including the thyroid, liver, and pancreas, are correctly specified. The phenotype observed is recapitulated by an endoderm-restricted deletion of β-catenin, demonstrating that Wnt2/2b signaling through the canonical Wnt pathway is required to specify lung endoderm progenitors within the foregut. Moreover, activation of canonical Wnt/β-catenin signaling results in the reprogramming of esophagus and stomach endoderm to a lung endoderm progenitor fate. Together, these da! ta reveal that canonical Wnt2/2b signaling is required for the specification of lung endoderm progenitors in the developing foregut. - Systematic Analysis of the Transcriptional Switch Inducing Migration of Border Cells
- Dev Cell 17(2):299 (2009)
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