Developmental Cell

Role of PINK1 Binding to the TOM Complex and Alternate Intracellular Membranes in Recruitment and Activation of the E3 Ligase Parkin.

Publication Date: 2012 Jan 24 PMID: 22280891
Authors: Lazarou, M. - Jin, S. M. - Kane, L. A. - Youle, R. J.
Journal: Dev Cell

Mutations in the mitochondrial kinase PINK1 and the cytosolic E3 ligase Parkin can cause Parkinson's disease. Damaged mitochondria accumulate PINK1 on the outer membrane where, dependent on kinase activity, it recruits and activates Parkin to induce mitophagy, potentially maintaining organelle fidelity. How PINK1 recruits Parkin is unknown. We show that endogenous PINK1 forms a 700 kDa complex with the translocase of the outer membrane (TOM) selectively on depolarized mitochondria whereas PINK1 ectopically targeted to the outer membrane retains association with TOM on polarized mitochondria. Inducibly targeting PINK1 to peroxisomes or lysosomes, which lack a TOM complex, recruits Parkin and activates ubiquitin ligase activity on the respective organelles. Once there, Parkin induces organelle selective autophagy of peroxisomes but not lysosomes. We propose that the association of PINK1 with the TOM complex allows rapid reimport of PINK1 to rescue repolarized mitochondria from mitophagy, and discount mitochondrial-specific factors for Parkin translocation and activation.

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The Cell Adhesion Molecule Echinoid Functions as a Tumor Suppressor and Upstream Regulator of the Hippo Signaling Pathway.

Publication Date: 2012 Jan 24 PMID: 22280890
Authors: Yue, T. - Tian, A. - Jiang, J.
Journal: Dev Cell

The Hippo (Hpo) signaling pathway controls tissue growth and organ size in species ranging from Drosophila to mammals and is deregulated in a wide range of human cancers. The core pathway consists of the Hpo/Warts (Wts) kinase cassette that phosphorylates and inactivates the transcriptional coactivator Yorkie (Yki). Here, we report that Echinoid (Ed), an immunoglobulin domain-containing cell adhesion molecule, acts as an upstream regulator of the Hpo pathway. Loss of Ed compromises Yki phosphorylation, resulting in elevated Yki activity that increases Hpo target gene expression and drives tissue overgrowth. Ed physically interacts with and stabilizes the Hpo-binding partner Salvador (Sav) at adherens junctions. Ed/Sav interaction is promoted by cell-cell contact and requires dimerization of Ed cytoplasmic domain. Overexpression of Sav or dimerized Ed cytoplasmic domain suppressed loss-of-Ed phenotypes. We propose that Ed may link cell-cell contact to Hpo signaling through binding and stabilizing Sav, thus modulating the Hpo kinase activity.

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A Change in Nuclear Pore Complex Composition Regulates Cell Differentiation.

Publication Date: 2012 Jan 18 PMID: 22264802
Authors: D'Angelo, M. A. - Gomez-Cavazos, J. S. - Mei, A. - Lackner, D. H. - Hetzer, M. W.
Journal: Dev Cell

Nuclear pore complexes (NPCs) are built from approximately 30 different proteins called nucleoporins or Nups. Previous studies have shown that several Nups exhibit cell-type-specific expression and that mutations in NPC components result in tissue-specific diseases. Here we show that a specific change in NPC composition is required for both myogenic and neuronal differentiation. The transmembrane nucleoporin Nup210 is absent in proliferating myoblasts and embryonic stem cells (ESCs) but becomes expressed and incorporated into NPCs during cell differentiation. Preventing Nup210 production by RNAi blocks myogenesis and the differentiation of ESCs into neuroprogenitors. We found that the addition of Nup210 to NPCs does not affect nuclear transport but is required for the induction of genes that are essential for cell differentiation. Our results identify a single change in NPC composition as an essential step in cell differentiation and establish a role for Nup210 in gene expression regulation and cell fate determination.

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Secreted VAPB/ALS8 Major Sperm Protein Domains Modulate Mitochondrial Localization and Morphology via Growth Cone Guidance Receptors.

Publication Date: 2012 Jan 18 PMID: 22264801
Authors: Han, S. M. - Tsuda, H. - Yang, Y. - Vibbert, J. - Cottee, P. - Lee, S. J. - Winek, J. - Haueter, C. - Bellen, H. J. - Miller, M. A.
Journal: Dev Cell

The VAPB/ALS8 major sperm protein domain (vMSP) is implicated in amyotrophic lateral sclerosis and spinal muscular atrophy, yet its function in the nervous system is not well understood. In Caenorhabditis elegans and Drosophila, the vMSP is cleaved from its transmembrane anchor and secreted in a cell type-specific fashion. We show that vMSPs secreted by neurons act on Lar-like protein-tyrosine phosphatase and Roundabout growth cone guidance receptors expressed in striated muscle. This signaling pathway promotes Arp2/3-dependent actin remodeling and mitochondrial localization to actin-rich muscle I-bands. C. elegans VAPB mutants have mitochondrial localization, morphology, mobility, and fission/fusion defects that are suppressed by Lar-like receptor or Arp2/3 inactivation. Hence, growth cone guidance receptor pathways that remodel the actin cytoskeleton have unanticipated effects on mitochondrial dynamics. We propose that neurons secrete vMSPs to promote striated muscle energy production and metabolism, in part through the regulation of mitochondrial localization and function.

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Canonical Wnt Signaling Dynamically Controls Multiple Stem Cell Fate Decisions during Vertebrate Body Formation.

Publication Date: 2012 Jan 17 PMID: 22264734
Authors: Martin, B. L. - Kimelman, D.
Journal: Dev Cell

The vertebrate body forms in an anterior-to-posterior progression, driven by a population of undifferentiated cells at the posterior-most end of the embryo. Recent studies have demonstrated that these undifferentiated cells are multipotent stem cells, suggesting that local signaling factors specify cell fate. However, the mechanism of cell fate specification during this process is unknown. Using a combination of single cell transplantation and newly developed cell-autonomous inducible Wnt inhibitor and activator transgenic zebrafish lines, we show that canonical Wnt signaling is continuously necessary and sufficient to specify mesoderm from a bipotential neural/mesodermal precursor. Surprisingly, we also find that Wnt signaling functions subsequently within the mesoderm to specify somites instead of posterior vascular endothelium. Our results demonstrate that dynamic local Wnt signaling cues specify germ layer contribution and mesodermal tissue type specification of multipotent stem cells throughout the formation of the early vertebrate embryonic body.

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Different auxin response machineries control distinct cell fates in the early plant embryo.

Publication Date: 2012 Jan 17 PMID: 22264733
Authors: Rademacher, E. H. - Lokerse, A. S. - Schlereth, A. - Llavata-Peris, C. I. - Bayer, M. - Kientz, M. - Freire Rios, A. - Borst, J. W. - Lukowitz, W. - Jurgens, G. - Weijers, D.
Journal: Dev Cell

The cell types of the plant root are first specified early during embryogenesis and are maintained throughout plant life. Auxin plays an essential role in embryonic root initiation, in part through the action of the ARF5/MP transcription factor and its auxin-labile inhibitor IAA12/BDL. MP and BDL function in embryonic cells but promote auxin transport to adjacent extraembryonic suspensor cells, including the quiescent center precursor (hypophysis). Here we show that a cell-autonomous auxin response within this cell is required for root meristem initiation. ARF9 and redundant ARFs, and their inhibitor IAA10, act in suspensor cells to mediate hypophysis specification and, surprisingly, also to prevent transformation to embryo identity. ARF misexpression, and analysis of the short suspensor mutant, demonstrates that lineage-specific expression of these ARFs is required for normal embryo development. These results imply the existence of a prepattern for a cell-type-specific auxin response that underlies the auxin-dependent specification of embryonic cell types.

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Tissue-Specific Coupling between Insulin/IGF and TORC1 Signaling via PRAS40 in Drosophila.

Publication Date: 2012 Jan 17 PMID: 22264732
Authors: Pallares-Cartes, C. - Cakan-Akdogan, G. - Teleman, A. A.
Journal: Dev Cell

PRAS40 has recently been identified as a protein that couples insulin/IGF signaling (IIS) to TORC1 activation in cell culture; however, the physiological function of PRAS40 is not known. In this study, we investigate flies lacking PRAS40. Surprisingly, we find both biochemically and genetically that PRAS40 couples IIS to TORC1 activation in a tissue-specific manner, regulating TORC1 activity in ovaries but not in other tissues of the animal. PRAS40 thereby regulates fertility but not growth of the fly, allowing distinct physiological functions of TORC1 to be uncoupled. We also show that the main function of PRAS40 in vivo is to regulate TORC1 activity, and not to act as a downstream target and effector of TORC1. Finally, this work sheds some light on the question of whether TORC1 activity is coupled to IIS in vivo.

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VEGF-Induced Vascular Permeability Is Mediated by FAK.

Publication Date: 2012 Jan 17 PMID: 22264731
Authors: Chen, X. L. - Nam, J. O. - Jean, C. - Lawson, C. - Walsh, C. T. - Goka, E. - Lim, S. T. - Tomar, A. - Tancioni, I. - Uryu, S. - Guan, J. L. - Acevedo, L. M. - Weis, S. M. - Cheresh, D. A. - Schlaepfer, D. D.
Journal: Dev Cell

Endothelial cells (ECs) form cell-cell adhesive junctional structures maintaining vascular integrity. This barrier is dynamically regulated by vascular endothelial growth factor (VEGF) receptor signaling. We created an inducible knockin mouse model to study the contribution of the integrin-associated focal adhesion tyrosine kinase (FAK) signaling on vascular function. Here we show that genetic or pharmacological FAK inhibition in ECs prevents VEGF-stimulated permeability downstream of VEGF receptor or Src tyrosine kinase activation in vivo. VEGF promotes tension-independent FAK activation, rapid FAK localization to cell-cell junctions, binding of the FAK FERM domain to the vascular endothelial cadherin (VE-cadherin) cytoplasmic tail, and direct FAK phosphorylation of beta-catenin at tyrosine-142 (Y142) facilitating VE-cadherin-beta-catenin dissociation and EC junctional breakdown. Kinase inhibited FAK is in a closed conformation that prevents VE-cadherin association and limits VEGF-stimulated beta-catenin Y142 phosphorylation. Our studies establish a role for FAK as an essential signaling switch within ECs regulating adherens junction dynamics.

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Phosphoinositide signaling regulates the exocyst complex and polarized integrin trafficking in directionally migrating cells.

Publication Date: 2012 Jan 17 PMID: 22264730
Authors: Thapa, N. - Sun, Y. - Schramp, M. - Choi, S. - Ling, K. - Anderson, R. A.
Journal: Dev Cell

Polarized delivery of signaling and adhesion molecules to the leading edge is required for directional migration of cells. Here, we describe a role for the PIP(2)-synthesizing enzyme, PIPKIgammai2, in regulation of exocyst complex control of cell polarity and polarized integrin trafficking during migration. Loss of PIPKIgammai2 impaired directional migration, formation of cell polarity, and integrin trafficking to the leading edge. Upon initiation of directional migration, PIPKIgammai2 via PIP(2) generation controls the integration of the exocyst complex into an integrin-containing trafficking compartment that requires the talin-binding ability of PIPKIgammai2, and talin for integrin recruitment to the leading edge. A PIP(2) requirement is further emphasized by inhibition of PIPKIgammai2-regulated directional migration by an Exo70 mutant deficient in PIP(2) binding. These results reveal how phosphoinositide generation orchestrates polarized trafficking of integrin in coordination with talin that links integrins to the actin cytoskeleton, processes that are required for directional migration.

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A Gbetagamma Effector, ElmoE, Transduces GPCR Signaling to the Actin Network during Chemotaxis.

Publication Date: 2012 Jan 17 PMID: 22264729
Authors: Yan, J. - Mihaylov, V. - Xu, X. - Brzostowski, J. A. - Li, H. - Liu, L. - Veenstra, T. D. - Parent, C. A. - Jin, T.
Journal: Dev Cell

Activation of G protein-coupled receptors (GPCRs) leads to the dissociation of heterotrimeric G-proteins into Galpha and Gbetagamma subunits, which go on to regulate various effectors involved in a panoply of cellular responses. During chemotaxis, Gbetagamma subunits regulate actin assembly and migration, but the protein(s) linking Gbetagamma to the actin cytoskeleton remains unknown. Here, we identified a Gbetagamma effector, ElmoE in Dictyostelium, and demonstrated that it is required for GPCR-mediated chemotaxis. Remarkably, ElmoE associates with Gbetagamma and Dock-like proteins to activate the small GTPase Rac, in a GPCR-dependent manner, and also associates with Arp2/3 complex and F-actin. Thus, ElmoE serves as a link between chemoattractant GPCRs, G-proteins and the actin cytoskeleton. The pathway, consisting of GPCR, Gbetagamma, Elmo/Dock, Rac, and Arp2/3, spatially guides the growth of dendritic actin networks in pseudopods of eukaryotic cells during chemotaxis.

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Expanding the morphogenetic repertoire: perspectives from the Drosophila egg.

Publication Date: 2012 Jan 17 PMID: 22264728
Authors: Bilder, D. - Haigo, S. L.
Journal: Dev Cell

Tissue and organ architectures are incredibly diverse, yet our knowledge of the morphogenetic behaviors that generate them is relatively limited. Recent studies have revealed unexpected mechanisms that drive axis elongation in the Drosophila egg, including an unconventional planar polarity signaling pathway, a distinctive type of morphogenetic movement termed "global tissue rotation," a molecular corset-like role of extracellular matrix, and oscillating basal cellular contractions. We review here what is known about Drosophila egg elongation, compare it to other instances of morphogenesis, and highlight several issues of general developmental relevance.

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All's Well that Ends Well: Arresting Cell Proliferation in Leaves.

Publication Date: 2012 Jan 17 PMID: 22264727
Authors: Lenhard, M.
Journal: Dev Cell

The transition from cell proliferation to cell expansion is critical for determining leaf size. Andriankaja et al. (2012) demonstrate that in leaves of dicotyledonous plants, a basal proliferation zone is maintained for several days before abruptly disappearing, and that chloroplast differentiation is required to trigger the onset of cell expansion.

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Targeting mechanisms in myelinated axons: not all nodes are created equal.

Publication Date: 2012 Jan 17 PMID: 22264726
Authors: Lyons, D. A. - Talbot, W. S.
Journal: Dev Cell

A recent Neuron paper by Zhang et al. (2012) reveals how ion channels and adhesion molecules essential for rapid nerve conduction in vertebrates are differentially targeted to nodes of Ranvier. Moreover, distinct mechanisms regulate initial clustering and maintenance of specific nodal components.

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Contact is repulsive, but please note the "enclosed".

Publication Date: 2012 Jan 17 PMID: 22264725
Authors: Burgess, R. W. - Garrett, A. M. - Tadenev, A. L.
Journal: Dev Cell

Previous models of neuronal dendrite arborization suggested that contact-dependent self-avoidance between dendrite branches prevents self-crossings within the arbor. Two papers in Neuron show how integrin-mediated adhesion to the extracellular matrix restricts dendrites to a two-dimensional space to optimize this mechanism (Han et al., 2012; Kim et al., 2012).

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Spurred by resistance: mechanosensation in collective migration.

Publication Date: 2012 Jan 17 PMID: 22264724
Authors: Behrndt, M. - Heisenberg, C. P.
Journal: Dev Cell

How cells orchestrate their behavior during collective migration is a long-standing question. Using magnetic tweezers to apply mechanical stimuli to Xenopus mesendoderm cells, Weber et al. (2012) now reveal, in this issue of Developmental Cell, a cadherin-mediated mechanosensitive response that promotes cell polarization and movement persistence during the collective mesendoderm migration in gastrulation.

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Centromeres Poised En Pointe: CDKs Put a Hold on CENP-A Assembly.

Publication Date: 2012 Jan 17 PMID: 22264723
Authors: Stimpson, K. M. - Sullivan, B. A.
Journal: Dev Cell

Eukaryotic centromeres are propagated by incorporation of the centromere-specific histone CENP-A into centromeric chromatin. Silva et al. (2012) now show that cyclin-dependent kinases (CDKs) hold the CENP-A assembly machinery in an inactive state until mitotic exit and entry into G1, at which time new CENP-A is loaded.

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Exit from Proliferation during Leaf Development in Arabidopsis thaliana: A Not-So-Gradual Process.

Publication Date: 2012 Jan 17 PMID: 22227310
Authors: Andriankaja, M. - Dhondt, S. - De Bodt, S. - Vanhaeren, H. - Coppens, F. - De Milde, L. - Muhlenbock, P. - Skirycz, A. - Gonzalez, N. - Beemster, G. T. - Inze, D.
Journal: Dev Cell

Early leaf growth is sustained by cell proliferation and subsequent cell expansion that initiates at the leaf tip and proceeds in a basipetal direction. Using detailed kinematic and gene expression studies to map these stages during early development of the third leaf of Arabidopsis thaliana, we showed that the cell-cycle arrest front did not progress gradually down the leaf, but rather was established and abolished abruptly. Interestingly, leaf greening and stomatal patterning followed a similar basipetal pattern, but proliferative pavement cell and formative meristemoid divisions were uncoordinated in respect to onset and persistence. Genes differentially expressed during the transition from cell proliferation to expansion were enriched in genes involved in cell cycle, photosynthesis, and chloroplast retrograde signaling. Proliferating primordia treated with norflurazon, a chemical inhibitor of retrograde signaling, showed inhibited onset of cell expansion. Hence, differentiation of the photosynthetic machinery is important for regulating the exit from proliferation. VIDEO ABSTRACT:

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Daam2 Is Required for Dorsal Patterning via Modulation of Canonical Wnt Signaling in the Developing Spinal Cord.

Publication Date: 2012 Jan 17 PMID: 22227309
Authors: Lee, H. K. - Deneen, B.
Journal: Dev Cell

The Daam family of proteins consists of Daam1 and Daam2. Although Daam1 participates in noncanonical Wnt signaling during gastrulation, Daam2 function remains completely uncharacterized. Here we describe the role of Daam2 in canonical Wnt signal transduction during spinal cord development. Loss-of-function studies revealed that Daam2 is required for dorsal progenitor identities and canonical Wnt signaling. These phenotypes are rescued by beta-catenin, demonstrating that Daam2 functions in dorsal patterning through the canonical Wnt pathway. Complementary gain-of-function studies demonstrate that Daam2 amplifies Wnt signaling by potentiating ligand activation. Biochemical examination found that Daam2 association with Dvl3 is required for Wnt activity and dorsal patterning. Moreover, Daam2 stabilizes Dvl3/Axin2 binding, resulting in enhanced intracellular assembly of Dvl3/Axin2 complexes. These studies demonstrate that Daam2 modulates the formation of Wnt receptor complexes, revealing new insight into the functional diversity of Daam proteins and how canonical Wnt signaling contributes to pattern formation in the developing spinal cord.

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Angiogenic Sprouting Requires the Fine Tuning of Endothelial Cell Cohesion by the Raf-1/Rok-alpha Complex.

Publication Date: 2012 Jan 17 PMID: 22209329
Authors: Wimmer, R. - Cseh, B. - Maier, B. - Scherrer, K. - Baccarini, M.
Journal: Dev Cell

Sprouting angiogenesis, crucial for the development of new blood vessels, is a prime example of collective migration in which endothelial cells migrate as a group joined via cadherin-containing adherens junctions (AJ). The actomyosin apparatus is connected to AJ and generates contractile forces, which, depending on their strength and duration, increase or decrease cell cohesion. Thus, appropriate spatiotemporal control of junctional myosin is critical, but the mechanisms underlying it are incompletely understood. We show that Raf-1 is an essential component of this regulatory network and that its ablation impairs endothelial cell cohesion, sprouting, and tumor-induced angiogenesis. Mechanistically, Raf-1 is recruited to VE-cadherin complexes by a mechanism involving the small G protein Rap1 and is required to bring the Rho effector Rok-alpha to nascent AJs. This Raf-1-mediated fine tuning of Rok-alpha signaling allows the activation of junctional myosin and the timely maturation of AJ essential for maintaining cell cohesion during sprouting angiogenesis.

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DUX4 Activates Germline Genes, Retroelements, and Immune Mediators: Implications for Facioscapulohumeral Dystrophy.

Publication Date: 2012 Jan 17 PMID: 22209328
Authors: Geng, L. N. - Yao, Z. - Snider, L. - Fong, A. P. - Cech, J. N. - Young, J. M. - van der Maarel, S. M. - Ruzzo, W. L. - Gentleman, R. C. - Tawil, R. - Tapscott, S. J.
Journal: Dev Cell

Facioscapulohumeral dystrophy (FSHD) is one of the most common inherited muscular dystrophies. The causative gene remains controversial and the mechanism of pathophysiology unknown. Here we identify genes associated with germline and early stem cell development as targets of the DUX4 transcription factor, a leading candidate gene for FSHD. The genes regulated by DUX4 are reliably detected in FSHD muscle but not in controls, providing direct support for the model that misexpression of DUX4 is a causal factor for FSHD. Additionally, we show that DUX4 binds and activates LTR elements from a class of MaLR endogenous primate retrotransposons and suppresses the innate immune response to viral infection, at least in part through the activation of DEFB103, a human defensin that can inhibit muscle differentiation. These findings suggest specific mechanisms of FSHD pathology and identify candidate biomarkers for disease diagnosis and progression.

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Rab25 and CLIC3 Collaborate to Promote Integrin Recycling from Late Endosomes/Lysosomes and Drive Cancer Progression.

Publication Date: 2012 Jan 17 PMID: 22197222
Authors: Dozynkiewicz, M. A. - Jamieson, N. B. - Macpherson, I. - Grindlay, J. - van den Berghe, P. V. - von Thun, A. - Morton, J. P. - Gourley, C. - Timpson, P. - Nixon, C. - McKay, C. J. - Carter, R. - Strachan, D. - Anderson, K. - Sansom, O. J. - Caswell, P. T. - Norman, J. C.
Journal: Dev Cell

Here we show that Rab25 permits the sorting of ligand-occupied, active-conformation alpha5beta1 integrin to late endosomes/lysosomes. Photoactivation and biochemical approaches show that lysosomally targeted integrins are not degraded but are retrogradely transported and recycled to the plasma membrane at the back of invading cells. This requires CLIC3, a protein upregulated in Rab25-expressing cells and tumors, which colocalizes with active alpha5beta1 in late endosomes/lysosomes. CLIC3 is necessary for release of the cell rear during migration on 3D matrices and is required for invasion and maintenance of active Src signaling in organotypic microenvironments. CLIC3 expression predicts lymph node metastasis and poor prognosis in operable cases of pancreatic ductal adenocarcinoma (PDAC). The identification of CLIC3 as a regulator of a recycling pathway and as an independent prognostic indicator in PDAC highlights the importance of active integrin trafficking as a potential drive to cancer progression in vivo.

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UTX, a Histone H3-Lysine 27 Demethylase, Acts as a Critical Switch to Activate the Cardiac Developmental Program.

Publication Date: 2012 Jan 17 PMID: 22192413
Authors: Lee, S. - Lee, J. W. - Lee, S. K.
Journal: Dev Cell

The removal of histone H3 lysine27 (H3K27) trimethylation mark is important for the robust induction of many cell type-specific genes during differentiation. Here we show that UTX, a H3K27 demethylase, acts as a critical switch to promote a cardiac-specific gene program. UTX-deficient ESCs failed to develop heart-like rhythmic contractions under a cardiac differentiation condition. UTX-deficient mice show severe defects in heart development and embryonic lethality. We found that UTX is recruited to cardiac-specific enhancers by associating with core cardiac transcription factors and demethylates H3K27 residues in cardiac genes. In addition, UTX facilitates the recruitment of Brg1 to the cardiac-specific enhancers. Together, our data reveal key roles for UTX in a timely transition from poised to active chromatin in cardiac genes during heart development and a fundamental mechanism by which a H3K27 demethylase triggers tissue-specific chromatin changes.

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The gamma-Secretase Cleavage Product of Polycystin-1 Regulates TCF and CHOP-Mediated Transcriptional Activation through a p300-Dependent Mechanism.

Publication Date: 2012 Jan 17 PMID: 22178500
Authors: Merrick, D. - Chapin, H. - Baggs, J. E. - Yu, Z. - Somlo, S. - Sun, Z. - Hogenesch, J. B. - Caplan, M. J.
Journal: Dev Cell

Mutations in Pkd1, encoding polycystin-1 (PC1), cause autosomal-dominant polycystic kidney disease (ADPKD). We show that the carboxy-terminal tail (CTT) of PC1 is released by gamma-secretase-mediated cleavage and regulates the Wnt and CHOP pathways by binding the transcription factors TCF and CHOP, disrupting their interaction with the common transcriptional coactivator p300. Loss of PC1 causes increased proliferation and apoptosis, while reintroducing PC1-CTT into cultured Pkd1 null cells reestablishes normal growth rate, suppresses apoptosis, and prevents cyst formation. Inhibition of gamma-secretase activity impairs the ability of PC1 to suppress growth and apoptosis and leads to cyst formation in cultured renal epithelial cells. Expression of the PC1-CTT is sufficient to rescue the dorsal body curvature phenotype in zebrafish embryos resulting from either gamma-secretase inhibition or suppression of Pkd1 expression. Thus, gamma-secretase-dependent release of the PC1-CTT creates a protein fragment whose expression is sufficient to suppress ADPKD-related phenotypes in vitro and in vivo.

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Tre1 GPCR Signaling Orients Stem Cell Divisions in the Drosophila Central Nervous System.

Publication Date: 2012 Jan 17 PMID: 22178499
Authors: Yoshiura, S. - Ohta, N. - Matsuzaki, F.
Journal: Dev Cell

During development, directional cell division is a major mechanism for establishing the orientation of tissue growth. Drosophila neuroblasts undergo asymmetric divisions perpendicular to the overlying epithelium to produce descendant neurons on the opposite side, thereby orienting initial neural tissue growth. However, the mechanism remains elusive. We provide genetic evidence that extrinsic GPCR signaling determines the orientation of cortical polarity underlying asymmetric divisions of neuroblasts relative to the epithelium. The GPCR Tre1 activates the G protein oalpha subunit in neuroblasts by interacting with the epithelium to recruit Pins, which regulates spindle orientation. Because Pins associates with the Par-complex via Inscuteable, Tre1 consequently recruits the polarity complex to orthogonally orient the polarity axis to the epithelium. Given the universal role of the Par complex in cellular polarization, we propose that the GPCR-Pins system is a comprehensive mechanism controlling tissue polarity by orienting polarized stem cells and their divisions.

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A mechanoresponsive cadherin-keratin complex directs polarized protrusive behavior and collective cell migration.

Publication Date: 2012 Jan 17 PMID: 22169071
Authors: Weber, G. F. - Bjerke, M. A. - Desimone, D. W.
Journal: Dev Cell

Collective cell migration requires maintenance of adhesive contacts between adjacent cells, coordination of polarized cell protrusions, and generation of propulsive traction forces. We demonstrate that mechanical force applied locally to C-cadherins on single Xenopus mesendoderm cells is sufficient to induce polarized cell protrusion and persistent migration typical of individual cells within a collectively migrating tissue. Local tension on cadherin adhesions induces reorganization of the keratin intermediate filament network toward these stressed sites. Plakoglobin, a member of the catenin family, is localized to cadherin adhesions under tension and is required for both mechanoresponsive cell behavior and assembly of the keratin cytoskeleton at the rear of these cells. Local tugging forces on cadherins occur in vivo through interactions with neighboring cells, and these forces result in coordinate changes in cell protrusive behavior. Thus, cadherin-dependent force-inducible regulation of cell polarity in single mesendoderm cells represents an emergent property of the intact tissue. VIDEO ABSTRACT:

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Cdk activity couples epigenetic centromere inheritance to cell cycle progression.

Publication Date: 2012 Jan 17 PMID: 22169070
Authors: Silva, M. C. - Bodor, D. L. - Stellfox, M. E. - Martins, N. M. - Hochegger, H. - Foltz, D. R. - Jansen, L. E.
Journal: Dev Cell

Centromeres form the site of chromosome attachment to microtubules during mitosis. Identity of these loci is maintained epigenetically by nucleosomes containing the histone H3 variant CENP-A. Propagation of CENP-A chromatin is uncoupled from DNA replication initiating only during mitotic exit. We now demonstrate that inhibition of Cdk1 and Cdk2 activities is sufficient to trigger CENP-A assembly throughout the cell cycle in a manner dependent on the canonical CENP-A assembly machinery. We further show that the key CENP-A assembly factor Mis18BP1(HsKNL2) is phosphorylated in a cell cycle-dependent manner that controls its centromere localization during mitotic exit. These results strongly support a model in which the CENP-A assembly machinery is poised for activation throughout the cell cycle but kept in an inactive noncentromeric state by Cdk activity during S, G2, and M phases. Alleviation of this inhibition in G1 phase ensures tight coupling between DNA replication, cell division, and subsequent centromere maturation.

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