Developmental Cell

Focal Defects in Single-Celled Tubes Mutant for Cerebral Cavernous Malformation 3, GCKIII, or NSF2.

Publication Date: 2013 Jun 10 PMID: 23763949
Authors: Song, Y. - Eng, M. - Ghabrial, A. S.
Journal: Dev Cell

Tubes of differing cellular architecture connect into networks. In the Drosophila tracheal system, two tube types connect within single cells (terminal cells); however, the genes that mediate this interconnection are unknown. Here we characterize two genes that are essential for this process: lotus, required for maintaining a connection between the tubes, and wheezy, required to prevent local tube dilation. We find that lotus encodes N-ethylmaleimide sensitive factor 2 (NSF2), whereas wheezy encodes Germinal center kinase III (GCKIII). GCKIIIs are effectors of Cerebral cavernous malformation 3 (CCM3), a protein mutated in vascular disease. Depletion of Ccm3 by RNA interference phenocopies wheezy; thus, CCM3 and GCKIII, which prevent capillary dilation in humans, prevent tube dilation in Drosophila trachea. Ectopic junctional and apical proteins are present in wheezy terminal cells, and we show that tube dilation is suppressed by reduction of NSF2, of the apical determinant Crumbs, or of septate junction protein Varicose.

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In Vivo analysis reveals a highly stereotypic morphogenetic pathway of vascular anastomosis.

Publication Date: 2013 Jun 10 PMID: 23763948
Authors: Lenard, A. - Ellertsdottir, E. - Herwig, L. - Krudewig, A. - Sauteur, L. - Belting, H. G. - Affolter, M.
Journal: Dev Cell

Organ formation and growth requires cells to organize into properly patterned three-dimensional architectures. Network formation within the vertebrate vascular system is driven by fusion events between nascent sprouts or between sprouts and pre-existing blood vessels. Here, we describe the cellular activities that occur during blood vessel anastomosis in the cranial vasculature of the zebrafish embryo. We show that the early steps of the fusion process involve endothelial cell recognition, de novo polarization of endothelial cells, and apical membrane invagination and fusion. These processes generate a unicellular tube, which is then transformed into a multicellular tube via cell rearrangements and cell splitting. This stereotypic series of morphogenetic events is typical for anastomosis in perfused sprouts. Vascular endothelial-cadherin plays an important role early in the anastomosis process and is required for filopodial tip cell interactions and efficient formation of a single contact site. VIDEO ABSTRACT:

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Switching axial progenitors from producing trunk to tail tissues in vertebrate embryos.

Publication Date: 2013 Jun 10 PMID: 23763947
Authors: Jurberg, A. D. - Aires, R. - Varela-Lasheras, I. - Novoa, A. - Mallo, M.
Journal: Dev Cell

The vertebrate body is made by progressive addition of new tissue from progenitors at the posterior embryonic end. Axial extension involves different mechanisms that produce internal organs in the trunk but not in the tail. We show that Gdf11 signaling is a major coordinator of the trunk-to-tail transition. Without Gdf11 signaling, the switch from trunk to tail is significantly delayed, and its premature activation brings the hindlimbs and cloaca next to the forelimbs, leaving extremely short trunks. Gdf11 activity includes activation of Isl1 to promote formation of the hindlimbs and cloaca-associated mesoderm as the most posterior derivatives of lateral mesoderm progenitors. Gdf11 also coordinates reallocation of bipotent neuromesodermal progenitors from the anterior primitive streak to the tail bud, in part by reducing the retinoic acid available to the progenitors. Our findings provide a perspective to understand the evolution of the vertebrate body plan.

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The art of choreographing asymmetric cell division.

Publication Date: 2013 Jun 10 PMID: 23763946
Authors: Li, R.
Journal: Dev Cell

Asymmetric cell division (ACD), a mechanism for cell-type diversification in both prokaryotes and eukaryotes, is accomplished through highly coordinated cell-fate segregation, genome partitioning, and cell division. Whereas important paradigms have arisen from the study of animal embryonic divisions, the strategies for choreographing the dynamic subprocesses are, in fact, highly varied. This review examines divergent mechanisms of ACD across different kingdoms. Examples discussed show that there is no obligatory hierarchy among the dynamic events and that asymmetry can emerge from each event, but cell polarization more often occurs as the initial instructive process for patterning ACD especially in the multicellular context.

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My brain told me to do it.

Publication Date: 2013 Jun 10 PMID: 23763945
Authors: Kong, J. H. - Butler, S. J. - Novitch, B. G.
Journal: Dev Cell

Voluntary motor control requires circuits in the brain to develop synchronously with spinal motor circuitry. In this issue of Developmental Cell,Reimer et al. (2013) demonstrate that this process is coordinated in zebrafish: dopamine released from descending projections modulates formation of motor neurons by attenuating the response of progenitors to Shh signaling.

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Vesicle transport and photoreceptor death: fishing for molecular links.

Publication Date: 2013 Jun 10 PMID: 23763944
Authors: Nagel-Wolfrum, K. - Wolfrum, U.
Journal: Dev Cell

Intracellular vesicle transport defects can induce retinal degeneration and photoreceptor cell death, but the molecular connections between these processes remains poorly understood. Reporting in Developmental Cell, Nishiwaki et al. (2013) suggest that a vesicle fusion cis-SNARE complex component translates vesicular transport defects into photoreceptor cell apoptosis.

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Oct4 Cell-Autonomously Promotes Primitive Endoderm Development in the Mouse Blastocyst.

Publication Date: 2013 Jun 4 PMID: 23747191
Authors: Frum, T. - Halbisen, M. A. - Wang, C. - Amiri, H. - Robson, P. - Ralston, A.
Journal: Dev Cell

In embryonic stem (ES) cells and in early mouse embryos, the transcription factor Oct4 is an essential regulator of pluripotency. Oct4 transcriptional targets have been described in ES cell lines; however, the molecular mechanisms by which Oct4 regulates establishment of pluripotency in the epiblast (EPI) have not been fully elucidated. Here, we show that neither maternal nor zygotic Oct4 is required for the formation of EPI cells in the blastocyst. Rather, Oct4 is first required for development of the primitive endoderm (PE), an extraembryonic lineage. EPI cells promote PE fate in neighboring cells by secreting Fgf4, and Oct4 is required for expression of Fgf4, but we show that Oct4 promotes PE development cell-autonomously, downstream of Fgf4 and Mapk. Finally, we show that Oct4 is required for the expression of multiple EPI and PE genes as well as multiple metabolic pathways essential for the continued growth of the preimplantation embryo.

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Ter94 ATPase Complex Targets K11-Linked Ubiquitinated Ci to Proteasomes for Partial Degradation.

Publication Date: 2013 Jun 4 PMID: 23747190
Authors: Zhang, Z. - Lv, X. - Yin, W. C. - Zhang, X. - Feng, J. - Wu, W. - Hui, C. C. - Zhang, L. - Zhao, Y.
Journal: Dev Cell

The Cubitus interruptus (Ci)/Gli family of transcription factors can be degraded either completely or partially from a full-length form (Ci155/GliFL) to a truncated repressor (Ci75/GliR) by proteasomes to mediate Hedgehog (Hh) signaling. The mechanism by which proteasomes distinguish ubiquitinated Ci/Gli to carry out complete versus partial degradation is not known. Here, we show that Ter94 ATPase and its mammalian counterpart, p97, are involved in processing Ci and Gli3 into Ci75 and Gli3R, respectively. Ter94 regulates the partial degradation of ubiquitinated Ci by Cul1-Slimb-based E3 ligase through its adaptors Ufd1-like and dNpl4. We demonstrate that Cul1-Slimb-based E3 ligase, but not Cul3-Rdx-based E3 ligase, modifies Ci by efficient addition of K11-linked ubiquitin chains. Ter94Ufd1-like/dNpl4 complex interacts directly with Cul1-Slimb, and, intriguingly, it prefers K11-linked ubiquitinated Ci. Thus, Ter94 ATPase and K11-linked ubiquitination in Ci contribute to the selectivity by proteasomes for partial degradation.

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The yeast alix homolog bro1 functions as a ubiquitin receptor for protein sorting into multivesicular endosomes.

Publication Date: 2013 Jun 10 PMID: 23726974
Authors: Pashkova, N. - Gakhar, L. - Winistorfer, S. C. - Sunshine, A. B. - Rich, M. - Dunham, M. J. - Yu, L. - Piper, R. C.
Journal: Dev Cell

Sorting of ubiquitinated membrane proteins into lumenal vesicles of multivesicular bodies is mediated by the Endosomal Sorting Complex Required for Transport (ESCRT) apparatus and accessory proteins such as Bro1, which recruits the deubiquitinating enzyme Doa4 to remove ubiquitin from cargo. Here we propose that Bro1 works as a receptor for the selective sorting of ubiquitinated cargos. We found synthetic genetic interactions between BRO1 and ESCRT-0, suggesting that Bro1 functions similarly to ESCRT-0. Multiple structural approaches demonstrated that Bro1 binds ubiquitin via the N-terminal trihelical arm of its middle V domain. Mutants of Bro1 that lack the ability to bind Ub were dramatically impaired in their ability to sort Ub-cargo membrane proteins, but only when combined with hypomorphic alleles of ESCRT-0. These data suggest that Bro1 and other Bro1 family members function in parallel with ESCRT-0 to recognize and sort Ub-cargos.

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TIGAR Is Required for Efficient Intestinal Regeneration and Tumorigenesis.

Publication Date: 2013 Jun 10 PMID: 23726973
Authors: Cheung, E. C. - Athineos, D. - Lee, P. - Ridgway, R. A. - Lambie, W. - Nixon, C. - Strathdee, D. - Blyth, K. - Sansom, O. J. - Vousden, K. H.
Journal: Dev Cell

Regulation of metabolic pathways plays an important role in controlling cell growth, proliferation, and survival. TIGAR acts as a fructose-2,6-bisphosphatase, potentially promoting the pentose phosphate pathway to produce NADPH for antioxidant function and ribose-5-phosphate for nucleotide synthesis. The functions of TIGAR were dispensable for normal growth and development in mice but played a key role in allowing intestinal regeneration in vivo and in ex vivo cultures, where growth defects due to lack of TIGAR were rescued by ROS scavengers and nucleosides. In a mouse intestinal adenoma model, TIGAR deficiency decreased tumor burden and increased survival, while elevated expression of TIGAR in human colon tumors suggested that deregulated TIGAR supports cancer progression. Our study demonstrates the importance of TIGAR in regulating metabolism for regeneration and cancer development and identifies TIGAR as a potential therapeutic target in diseases such as ulcerative colitis and intestinal cancer.

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Atrial Identity Is Determined by a COUP-TFII Regulatory Network.

Publication Date: 2013 May 28 PMID: 23725765
Authors: Wu, S. P. - Cheng, C. M. - Lanz, R. B. - Wang, T. - Respress, J. L. - Ather, S. - Chen, W. - Tsai, S. J. - Wehrens, X. H. - Tsai, M. J. - Tsai, S. Y.
Journal: Dev Cell

Atria and ventricles exhibit distinct molecular profiles that produce structural and functional differences between the two cardiac compartments. However, the factors that determine these differences remain largely undefined. Cardiomyocyte-specific COUP-TFII ablation produces ventricularized atria that exhibit ventricle-like action potentials, increased cardiomyocyte size, and development of extensive T tubules. Changes in atrial characteristics are accompanied by alterations of 2,584 genes, of which 81% were differentially expressed between atria and ventricles, suggesting that a major function of myocardial COUP-TFII is to determine atrial identity. Chromatin immunoprecipitation assays using E13.5 atria identified classic atrial-ventricular identity genes Tbx5, Hey2, Irx4, MLC2v, MLC2a, and MLC1a, among many other cardiac genes, as potential COUP-TFII direct targets. Collectively, our results reveal that COUP-TFII confers atrial identity through direct binding and by modulating expression of a broad spectrum of genes that have an impact on atrial development and function.

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The hippo effector yorkie controls normal tissue growth by antagonizing scalloped-mediated default repression.

Publication Date: 2013 May 28 PMID: 23725764
Authors: Koontz, L. M. - Liu-Chittenden, Y. - Yin, F. - Zheng, Y. - Yu, J. - Huang, B. - Chen, Q. - Wu, S. - Pan, D.
Journal: Dev Cell

The Hippo tumor suppressor pathway restricts tissue growth by inactivating the transcriptional coactivator Yki. Although Sd has been implicated as a DNA-binding transcription factor partner for Yki and can genetically account for gain-of-function Yki phenotypes, how Yki regulates normal tissue growth remains a long-standing puzzle because Sd, unlike Yki, is dispensable for normal growth in most Drosophila tissues. Here we show that the yki mutant phenotypes in multiple developmental contexts are rescued by inactivation of Sd, suggesting that Sd functions as a default repressor and that Yki promotes normal tissue growth by relieving Sd-mediated default repression. We further identify Tgi as a cofactor involved in Sd's default repressor function and demonstrate that the mammalian ortholog of Tgi potently suppresses the YAP oncoprotein in transgenic mice. These findings fill a major gap in Hippo-mediated transcriptional regulation and open up possibilities for modulating the YAP oncoprotein in cancer and regenerative medicine.

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The BH3-Only SNARE BNip1 Mediates Photoreceptor Apoptosis in Response to Vesicular Fusion Defects.

Publication Date: 2013 May 28 PMID: 23725763
Authors: Nishiwaki, Y. - Yoshizawa, A. - Kojima, Y. - Oguri, E. - Nakamura, S. - Suzuki, S. - Yuasa-Kawada, J. - Kinoshita-Kawada, M. - Mochizuki, T. - Masai, I.
Journal: Dev Cell

Intracellular vesicular transport is important for photoreceptor function and maintenance. However, the mechanism underlying photoreceptor degeneration in response to vesicular transport defects is unknown. Here, we report that photoreceptors undergo apoptosis in a zebrafish beta-soluble N-ethylmaleimide-sensitive factor attachment protein (beta-SNAP) mutant. beta-SNAP cooperates with N-ethylmaleimide-sensitive factor to recycle the SNAP receptor (SNARE), a key component of the membrane fusion machinery, by disassembling the cis-SNARE complex generated in the vesicular fusion process. We found that photoreceptor apoptosis in the beta-SNAP mutant was dependent on the BH3-only protein BNip1. BNip1 functions as a component of the syntaxin-18 SNARE complex and regulates retrograde transport from the Golgi to the endoplasmic reticulum. Failure to disassemble the syntaxin-18 cis-SNARE complex caused BNip1-dependent apoptosis. These data suggest that the syntaxin-18 cis-SNARE complex functions as an alarm factor that monitors vesicular fusion competence and that BNip1 transforms vesicular fusion defects into photoreceptor apoptosis.

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Deficiency of Lipid Phosphatase SHIP Enables Long-Term Reconstitution of Hematopoietic Inductive Bone Marrow Microenvironment.

Publication Date: 2013 May 28 PMID: 23725762
Authors: Liang, O. D. - Lu, J. - Nombela-Arrieta, C. - Zhong, J. - Zhao, L. - Pivarnik, G. - Mondal, S. - Chai, L. - Silberstein, L. E. - Luo, H. R.
Journal: Dev Cell

A dysfunctional bone marrow (BM) microenvironment is thought to contribute to the development of hematologic diseases. However, functional replacement of pathologic BM microenvironment through BM transplantation has not been possible. Furthermore, the study of hematopoietic inductive BM microenvironment is hampered by the lack of a functional nonhematopoietic reconstitution system. Here, we show that a deficiency of SH2-containing inositol-5'-phosphatase-1 (SHIP) in a nonhematopoietic host microenvironment enables its functional reconstitution by wild-type donor cells. This microenvironment reconstitution normalizes hematopoiesis in peripheral blood and BM and alleviates pathology of spleen and lung in the SHIP-deficient recipients. SHIP-deficient BM contains a significantly smaller population of multipotent stromal cells with distinct properties, which may contribute to the reconstitution by wild-type cells. We further demonstrate that it is the nonhematopoietic donor cells that are responsible for the reconstitution. Thus, we have established a nonhematopoietic BM microenvironment reconstitution system to functionally study specific cell types in hematopoietic niches.

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A close look at wiggly chromosomes.

Publication Date: 2013 May 28 PMID: 23725761
Authors: Bloom, K.
Journal: Dev Cell

In a recent issue of Cell, Fisher et al. (2013) use high-resolution time-lapse imaging to peer into bacterial genome (nucleoid) structure. The nucleoid, an elastic filament confined via an internal network, undergoes periodic fluctuations critical in relieving tension. Programmed tethers and their release highlight a primordial mechanical cycle for chromosome segregation.

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Filopodia: the cellular quills of hedgehog signaling?

Publication Date: 2013 May 28 PMID: 23725760
Authors: McMahon, A. P. - Hasso, S. M.
Journal: Dev Cell

Reporting in Nature, Sanders et al. (2013) implicate filopodial projections in Sonic hedgehog (Shh) patterning of the limb. Actin-based filopodia transport Shh from producing cells, while filopodia of responding cells bear Cdon and Boc: coreceptors in the Shh pathway. These findings suggest a new mechanism of ligand movement and transmission.

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Turtle origins: picking up speed.

Publication Date: 2013 May 28 PMID: 23725759
Authors: Gilbert, S. F. - Corfe, I.
Journal: Dev Cell

Genomes for three species of turtles were recently reported in Nature Genetics and Genome Biology. The findings of Wang et al. (2013) and Abramyan et al. (2013) place the turtles as a sister group to birds and crocodiles and offer clues to the origins of this group's remarkable physiological traits.

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Proteolytic Remodeling of the ECM and the Geometric Control of Stem Cell Fate.

Publication Date: 2013 May 28 PMID: 23725758
Authors: Keely, P. J.
Journal: Dev Cell

The mechanism by which mechanosignal transduction regulates stem cell fate is not well understood. In this issue of Developmental Cell, Tang et al. (2013) demonstrate that catalytic function of the metalloproteinase MT1-MMP controls ECM structure, cell shape, and an integrin/Rho/YAP-TAZ signaling axis to control osteogenic stem cell fate.

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Dopamine from the Brain Promotes Spinal Motor Neuron Generation during Development and Adult Regeneration.

Publication Date: 2013 Jun 10 PMID: 23707737
Authors: Reimer, M. M. - Norris, A. - Ohnmacht, J. - Patani, R. - Zhong, Z. - Dias, T. B. - Kuscha, V. - Scott, A. L. - Chen, Y. C. - Rozov, S. - Frazer, S. L. - Wyatt, C. - Higashijima, S. - Patton, E. E. - Panula, P. - Chandran, S. - Becker, T. - Becker, C. G.
Journal: Dev Cell

Coordinated development of brain stem and spinal target neurons is pivotal for the emergence of a precisely functioning locomotor system. Signals that match the development of these far-apart regions of the central nervous system may be redeployed during spinal cord regeneration. Here we show that descending dopaminergic projections from the brain promote motor neuron generation at the expense of V2 interneurons in the developing zebrafish spinal cord by activating the D4a receptor, which acts on the hedgehog pathway. Inhibiting this essential signal during early neurogenesis leads to a long-lasting reduction of motor neuron numbers and impaired motor responses of free-swimming larvae. Importantly, during successful spinal cord regeneration in adult zebrafish, endogenous dopamine promotes generation of spinal motor neurons, and dopamine agonists augment this process. Hence, we describe a supraspinal control mechanism for the development and regeneration of specific spinal cell types that uses dopamine as a signal.

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PTEN Controls Junction Lengthening and Stability during Cell Rearrangement in Epithelial Tissue.

Publication Date: 2013 Jun 10 PMID: 23707736
Authors: Bardet, P. L. - Guirao, B. - Paoletti, C. - Serman, F. - Leopold, V. - Bosveld, F. - Goya, Y. - Mirouse, V. - Graner, F. - Bellaiche, Y.
Journal: Dev Cell

Planar cell rearrangements control epithelial tissue morphogenesis and cellular pattern formation. They lead to the formation of new junctions whose length and stability determine the cellular pattern of tissues. Here, we show that during Drosophila wing development the loss of the tumor suppressor PTEN disrupts cell rearrangements by preventing the lengthening of newly formed junctions that become unstable and keep on rearranging. We demonstrate that the failure to lengthen and to stabilize is caused by the lack of a decrease of Myosin II and Rho-kinase concentration at the newly formed junctions. This defect results in a heterogeneous cortical contractility at cell junctions that disrupts regular hexagonal pattern formation. By identifying PTEN as a specific regulator of junction lengthening and stability, our results uncover how a homogenous distribution of cortical contractility along the cell cortex is restored during cell rearrangement to control the formation of epithelial cellular pattern.

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MT1-MMP-Dependent Control of Skeletal Stem Cell Commitment via a beta1-Integrin/YAP/TAZ Signaling Axis.

Publication Date: 2013 May 28 PMID: 23685250
Authors: Tang, Y. - Rowe, R. G. - Botvinick, E. L. - Kurup, A. - Putnam, A. J. - Seiki, M. - Weaver, V. M. - Keller, E. T. - Goldstein, S. - Dai, J. - Begun, D. - Saunders, T. - Weiss, S. J.
Journal: Dev Cell

In vitro, topographical and biophysical cues arising from the extracellular matrix (ECM) direct skeletal stem cell (SSC) commitment and differentiation. However, the mechanisms by which the SSC-ECM interface is regulated and the outcome of such interactions on stem cell fate in vivo remain unknown. Here we demonstrate that conditional deletion of the membrane-anchored metalloproteinase MT1-MMP (Mmp14) in mesenchymal progenitors, but not in committed osteoblasts, redirects SSC fate decisions from osteogenesis to adipo- and chondrogenesis. By effecting ECM remodeling, MT1-MMP regulates stem cell shape, thereby activating a beta1-integrin/RhoGTPase signaling cascade and triggering the nuclear localization of the transcriptional coactivators YAP and TAZ, which serve to control SSC lineage commitment. These data identify a critical MT1-MMP/integrin/YAP/TAZ axis operative in the stem cell niche that oversees SSC fate determination.

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Tissue Repair through Cell Competition and Compensatory Cellular Hypertrophy in Postmitotic Epithelia.

Publication Date: 2013 May 28 PMID: 23685249
Authors: Tamori, Y. - Deng, W. M.
Journal: Dev Cell

In multicellular organisms, tissue integrity and organ size are maintained through removal of aberrant or damaged cells and compensatory proliferation. Little is known, however, about this homeostasis system in postmitotic tissues, where tissue-intrinsic genetic programs constrain cell division and new cells no longer arise from stem cells. Here we show that, in postmitotic Drosophila follicular epithelia, aberrant but viable cells are eliminated through cell competition, and the resulting loss of local tissue volume triggers sporadic cellular hypertrophy to repair the tissue. This "compensatory cellular hypertrophy" is implemented by acceleration of the endocycle, a variant cell cycle composed of DNA synthesis and gap phases without mitosis, dependent on activation of the insulin/IGF-like signaling pathway. These results reveal a remarkable homeostatic mechanism in postmitotic epithelia that ensures not only elimination of aberrant cells through cell competition but also proper organ-size control that involves compensatory cellular hypertrophy induced by physical parameters.

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Viral Infection Controlled by a Calcium-Dependent Lipid-Binding Module in ALIX.

Publication Date: 2013 May 28 PMID: 23664863
Authors: Bissig, C. - Lenoir, M. - Velluz, M. C. - Kufareva, I. - Abagyan, R. - Overduin, M. - Gruenberg, J.
Journal: Dev Cell

ALIX plays a role in nucleocapsid release during viral infection, as does lysobisphosphatidic acid (LBPA). However, the mechanism remains unclear. Here we report that LBPA is recognized within an exposed site in ALIX Bro1 domain predicted by MODA, an algorithm for discovering membrane-docking areas in proteins. LBPA interactions revealed a strict requirement for a structural calcium tightly bound near the lipid interaction site. Unlike other calcium- and phospholipid-binding proteins, the all-helical triangle-shaped fold of the Bro1 domain confers selectivity for LBPA via a pair of hydrophobic residues in a flexible loop, which undergoes a conformational change upon membrane association. Both LBPA and calcium binding are necessary for endosome association and virus infection, as are ALIX ESCRT binding and dimerization capacity. We conclude that LBPA recruits ALIX onto late endosomes via the calcium-bound Bro1 domain, triggering a conformational change in ALIX to mediate the delivery of viral nucleocapsids to the cytosol during infection.

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G13 Controls Angiogenesis through Regulation of VEGFR-2 Expression.

Publication Date: 2013 May 28 PMID: 23664862
Authors: Sivaraj, K. K. - Takefuji, M. - Schmidt, I. - Adams, R. H. - Offermanns, S. - Wettschureck, N.
Journal: Dev Cell

At sites of angiogenesis, the expression of the key angiogenesis regulator vascular endothelial growth factor (VEGF) and its main receptor, VEGF receptor 2 (VEGFR-2), are strongly upregulated. Whereas the processes controlling VEGF expression are well described, the mechanisms underlying VEGFR-2 upregulation have remained unclear. We found that endothelial VEGFR-2 expression is strongly reduced in the absence of the G protein G13, resulting in an impaired responsiveness to VEGF-A, a phenotype that can be rescued by normalization of VEGFR-2 levels. G13-mediated VEGFR-2 expression involved activation of the small GTPase RhoA and transcription factor NF-kappaB, the latter acting via a specific binding site at position -84 of the VEGFR-2 promoter. Mice with endothelial cell-specific loss of G13 showed reduced VEGFR-2 expression at sites of angiogenesis and attenuated VEGF effects, resulting in impaired retinal angiogenesis and tumor vascularization. Taken together, we identified G-protein-mediated signaling via G13 as a critical regulator of VEGFR-2 expression during angiogenesis.

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