Developmental Cell

ADAM13 induces cranial neural crest by cleaving class B Ephrins and regulating Wnt signaling.

Publication Date: 2010 Aug 17 PMID: 20708595
Authors: Wei, S. - Xu, G. - Bridges, L. C. - Williams, P. - White, J. M. - DeSimone, D. W.
Journal: Dev Cell

The cranial neural crest (CNC) consists of multipotent embryonic cells that contribute to craniofacial structures and other cells and tissues of the vertebrate head. During embryogenesis, CNC is induced at the neural plate boundary through the interplay of several major signaling pathways. Here, we report that the metalloproteinase activity of ADAM13 is required for early induction of CNC in Xenopus. In both cultured cells and X. tropicalis embryos, membrane-bound Ephrins (Efns) B1 and B2 were identified as substrates for ADAM13. ADAM13 upregulates canonical Wnt signaling and early expression of the transcription factor snail2, whereas EfnB1 inhibits the canonical Wnt pathway and snail2 expression. We propose that by cleaving class B Efns, ADAM13 promotes canonical Wnt signaling and early CNC induction.

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Osteoblast precursors, but not mature osteoblasts, move into developing and fractured bones along with invading blood vessels.

Publication Date: 2010 Aug 17 PMID: 20708594
Authors: Maes, C. - Kobayashi, T. - Selig, M. K. - Torrekens, S. - Roth, S. I. - Mackem, S. - Carmeliet, G. - Kronenberg, H. M.
Journal: Dev Cell

During endochondral bone development, the first osteoblasts differentiate in the perichondrium surrounding avascular cartilaginous rudiments; the source of trabecular osteoblasts inside the later bone is, however, unknown. Here, we generated tamoxifen-inducible transgenic mice bred to Rosa26R-LacZ reporter mice to follow the fates of stage-selective subsets of osteoblast lineage cells. Pulse-chase studies showed that osterix-expressing osteoblast precursors, labeled in the perichondrium prior to vascular invasion of the cartilage, give rise to trabecular osteoblasts, osteocytes, and stromal cells inside the developing bone. Throughout the translocation, some precursors were found to intimately associate with invading blood vessels, in pericyte-like fashion. A similar coinvasion occurs during endochondral healing of bone fractures. In contrast, perichondrial mature osteoblasts did not exhibit perivascular localization and remained in the outer cortex of developing bones. These findings reveal the specific involvement of immature osteoblast precursors in the coupled vascular and osteogenic transformation essential to endochondral bone development and repair.

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Downstream of identity genes: muscle-type-specific regulation of the fusion process.

Publication Date: 2010 Aug 17 PMID: 20708593
Authors: Bataille, L. - Delon, I. - Da Ponte, J. P. - Brown, N. H. - Jagla, K.
Journal: Dev Cell

In all metazoan organisms, the diversification of cell types involves determination of cell fates and subsequent execution of specific differentiation programs. During Drosophila myogenesis, identity genes specify the fates of founder myoblasts, from which derive all individual larval muscles. Here, to understand how cell fate information residing within founders is translated during differentiation, we focus on three identity genes, eve, lb, and slou, and how they control the size of individual muscles by regulating the number of fusion events. They achieve this by setting expression levels of Mp20, Pax, and mspo, three genes that regulate actin dynamics and cell adhesion and, as we show here, modulate the fusion process in a muscle-specific manner. Thus, these data show how the identity information implemented by transcription factors is translated via target genes into cell-type-specific programs of differentiation.

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BMP signals promote proepicardial protrusion necessary for recruitment of coronary vessel and epicardial progenitors to the heart.

Publication Date: 2010 Aug 17 PMID: 20708592
Authors: Ishii, Y. - Garriock, R. J. - Navetta, A. M. - Coughlin, L. E. - Mikawa, T.
Journal: Dev Cell

The coronary vessels and epicardium arise from an extracardiac rudiment called the proepicardium. Failed fusion of the proepicardium to the heart results in severe coronary and heart defects. However, it is unknown how the proepicardium protrudes toward and attaches to the looping heart tube. Here, we show that ectopic expression of BMP ligands in the embryonic myocardium can cause proepicardial cells to target aberrant regions of the heart. Additionally, misexpression of a BMP antagonist, Noggin, suppresses proepicardium protrusion and contact with the heart. Finally, proepicardium explant preferentially expands toward a cocultured heart segment. This preference can be mimicked by BMP2/4 and suppressed by Noggin. These results support a model in which myocardium-derived BMP signals regulate the entry of coronary progenitors to the specific site of the heart by directing their morphogenetic movement.

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Hemocyte-secreted type IV collagen enhances BMP signaling to guide renal tubule morphogenesis in Drosophila.

Publication Date: 2010 Aug 17 PMID: 20708591
Authors: Bunt, S. - Hooley, C. - Hu, N. - Scahill, C. - Weavers, H. - Skaer, H.
Journal: Dev Cell

Details of the mechanisms that determine the shape and positioning of organs in the body cavity remain largely obscure. We show that stereotypic positioning of outgrowing Drosophila renal tubules depends on signaling in a subset of tubule cells and results from enhanced sensitivity to guidance signals by targeted matrix deposition. VEGF/PDGF ligands from the tubules attract hemocytes, which secrete components of the basement membrane to ensheath them. Collagen IV sensitizes tubule cells to localized BMP guidance cues. Signaling results in pathway activation in a subset of tubule cells that lead outgrowth through the body cavity. Failure of hemocyte migration, loss of collagen IV, or abrogation of BMP signaling results in tubule misrouting and defective organ shape and positioning. Such regulated interplay between cell-cell and cell-matrix interactions is likely to have wide relevance in organogenesis and congenital disease.

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The cytokinin-activated transcription factor ARR2 promotes plant immunity via TGA3/NPR1-dependent salicylic acid signaling in Arabidopsis.

Publication Date: 2010 Aug 17 PMID: 20708590
Authors: Choi, J. - Huh, S. U. - Kojima, M. - Sakakibara, H. - Paek, K. H. - Hwang, I.
Journal: Dev Cell

Cytokinins affect plant immunity to various pathogens; however, the mechanisms coupling plant-derived cytokinins to pathogen responses have been elusive. Here, we found that plant-derived cytokinins promote resistance of Arabidopsis to Pseudomonas syringae pv. tomato DC3000 (Pst). Modulated cytokinin levels or signaling activity in CKX- or IPT-overexpressing plants or in ahk2 ahk3 mutants correlated with altered resistance. In fact, the cytokinin-activated transcription factor ARR2 contributes specifically to Pst resistance. The salicylic acid (SA) response factor TGA3 binds ARR2, and mutation of TGA-binding cis-elements in the Pr1 promoter abolished cytokinin- and ARR2-dependent Pr1 activation. Cytokinin treatment did not increase pathogen resistance in tga3 plants, as the cytokinin-dependent induction of Pr1 was eliminated. Moreover, SA signaling enhanced binding of ARR2/TGA3 to the Pr1 promoter. Taken together, these results show that cytokinins modulate the SA signaling to augment resistance against Pst, a process in which the interaction between TGA3 and ARR2 is important.

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MIM and cortactin antagonism regulates ciliogenesis and hedgehog signaling.

Publication Date: 2010 Aug 17 PMID: 20708589
Authors: Bershteyn, M. - Atwood, S. X. - Woo, W. M. - Li, M. - Oro, A. E.
Journal: Dev Cell

The primary cilium is critical for transducing Sonic hedgehog (Shh) signaling, but the mechanisms of its transient assembly are poorly understood. Previously we showed that the actin regulatory protein Missing-in-Metastasis (MIM) regulates Shh signaling, but the nature of MIM's role was unknown. Here we show that MIM is required at the basal body of mesenchymal cells for cilia maintenance, Shh responsiveness, and de novo hair follicle formation. MIM knockdown results in increased Src kinase activity and subsequent hyperphosphorylation of the actin regulator Cortactin. Importantly, inhibition of Src or depletion of Cortactin compensates for the cilia defect in MIM knockdown cells, whereas overexpression of Src or phospho-mimetic Cortactin is sufficient to inhibit ciliogenesis. Our results suggest that MIM promotes ciliogenesis by antagonizing Src-dependent phosphorylation of Cortactin and describe a mechanism linking regulation of the actin cytoskeleton with ciliogenesis and Shh signaling during tissue regeneration.

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Focal adhesion kinase is required for intestinal regeneration and tumorigenesis downstream of Wnt/c-Myc signaling.

Publication Date: 2010 Aug 17 PMID: 20708588
Authors: Ashton, G. H. - Morton, J. P. - Myant, K. - Phesse, T. J. - Ridgway, R. A. - Marsh, V. - Wilkins, J. A. - Athineos, D. - Muncan, V. - Kemp, R. - Neufeld, K. - Clevers, H. - Brunton, V. - Winton, D. J. - Wang, X. - Sears, R. C. - Clarke, A. R. - Frame, M. C. - Sansom, O. J.
Journal: Dev Cell

The intestinal epithelium has a remarkable capacity to regenerate after injury and DNA damage. Here, we show that the integrin effector protein Focal Adhesion Kinase (FAK) is dispensable for normal intestinal homeostasis and DNA damage signaling, but is essential for intestinal regeneration following DNA damage. Given Wnt/c-Myc signaling is activated following intestinal regeneration, we investigated the functional importance of FAK following deletion of the Apc tumor suppressor protein within the intestinal epithelium. Following Apc loss, FAK expression increased in a c-Myc-dependent manner. Codeletion of Apc and Fak strongly reduced proliferation normally induced following Apc loss, and this was associated with reduced levels of phospho-Akt and suppression of intestinal tumorigenesis in Apc heterozygous mice. Thus, FAK is required downstream of Wnt Signaling, for Akt/mTOR activation, intestinal regeneration, and tumorigenesis. Importantly, this work suggests that FAK inhibitors may suppress tumorigenesis in patients at high risk of developing colorectal cancer.

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CLASP promotes microtubule rescue by recruiting tubulin dimers to the microtubule.

Publication Date: 2010 Aug 17 PMID: 20708587
Authors: Al-Bassam, J. - Kim, H. - Brouhard, G. - van Oijen, A. - Harrison, S. C. - Chang, F.
Journal: Dev Cell

Spatial regulation of microtubule (MT) dynamics contributes to cell polarity and cell division. MT rescue, in which a MT stops shrinking and reinitiates growth, is the least understood aspect of MT dynamics. Cytoplasmic Linker Associated Proteins (CLASPs) are a conserved class of MT-associated proteins that contribute to MT stabilization and rescue in vivo. We show here that the Schizosaccharomyces pombe CLASP, Cls1p, is a homodimer that binds an alphabeta-tubulin heterodimer through conserved TOG-like domains. In vitro, CLASP increases MT rescue frequency, decreases MT catastrophe frequency, and moderately decreases MT disassembly rate. CLASP binds stably to the MT lattice, recruits tubulin, and locally promotes rescues. Mutations in the CLASP TOG domains demonstrate that tubulin binding is critical for its rescue activity. We propose a mechanism for rescue in which CLASP-tubulin dimer complexes bind along the MT lattice and reverse MT depolymerization with their bound tubulin dimer.

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Condensins promote chromosome recoiling during early anaphase to complete sister chromatid separation.

Publication Date: 2010 Aug 17 PMID: 20708586
Authors: Renshaw, M. J. - Ward, J. J. - Kanemaki, M. - Natsume, K. - Nedelec, F. J. - Tanaka, T. U.
Journal: Dev Cell

Sister chromatid separation is initiated at anaphase onset by the activation of separase, which removes cohesins from chromosomes. However, it remains elusive how sister chromatid separation is completed along the entire chromosome length. Here we found that, during early anaphase in Saccharomyces cerevisiae, sister chromatids separate gradually from centromeres to telomeres, accompanied by regional chromosome stretching and subsequent recoiling. The stretching results from residual cohesion between sister chromatids, which prevents their immediate separation. This residual cohesion is at least partly dependent on cohesins that have escaped removal by separase at anaphase onset. Meanwhile, recoiling of a stretched chromosome region requires condensins and generates forces to remove residual cohesion. We provide evidence that condensins promote chromosome recoiling directly in vivo, which is distinct from their known function in resolving sister chromatids. Our work identifies residual sister chromatid cohesion during early anaphase and reveals condensins' roles in chromosome recoiling, which eliminates residual cohesion to complete sister chromatid separation.

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beta-Catenin primes organizer gene expression by recruiting a histone H3 arginine 8 methyltransferase, Prmt2.

Publication Date: 2010 Aug 17 PMID: 20708585
Authors: Blythe, S. A. - Cha, S. W. - Tadjuidje, E. - Heasman, J. - Klein, P. S.
Journal: Dev Cell

An emerging concept in development is that transcriptional poising presets patterns of gene expression in a manner that reflects a cell's developmental potential. However, it is not known how certain loci are specified in the embryo to establish poised chromatin architecture as the developmental program unfolds. We find that, in the context of transcriptional quiescence prior to the midblastula transition in Xenopus, dorsal specification by the Wnt/beta-catenin pathway is temporally uncoupled from the onset of dorsal target gene expression, and that beta-catenin establishes poised chromatin architecture at target promoters. beta-catenin recruits the arginine methyltransferase Prmt2 to target promoters, thereby establishing asymmetrically dimethylated H3 arginine 8 (R8). Recruitment of Prmt2 to beta-catenin target genes is necessary and sufficient to establish the dorsal developmental program, indicating that Prmt2-mediated histone H3(R8) methylation plays a critical role downstream of beta-catenin in establishing poised chromatin architecture and marking key organizer genes for later expression.

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An early developmental role for miRNAs in the maintenance of extraembryonic stem cells in the mouse embryo.

Publication Date: 2010 Aug 17 PMID: 20708584
Authors: Spruce, T. - Pernaute, B. - Di-Gregorio, A. - Cobb, B. S. - Merkenschlager, M. - Manzanares, M. - Rodriguez, T. A.
Journal: Dev Cell

The two first cell fate decisions taken in the mammalian embryo generate three distinct cell lineages: one embryonic, the epiblast, and two extraembryonic, the trophoblast and primitive endoderm. miRNAs are essential for early development, but it is not known if they are utilized in the same way in these three lineages. We find that in the pluripotent epiblast they inhibit apoptosis by blocking the expression of the proapoptotic protein Bcl2l11 (Bim) but play little role in the initiation of gastrulation. In contrast, in the trophectoderm, miRNAs maintain the trophoblast stem cell compartment by directly inhibiting expression of Cdkn1a (p21) and Cdkn1c (p57), and in the primitive endoderm, they prevent differentiation by maintaining ERK1/2 phosphorylation through blocking the expression of Mapk inhibitors. Therefore, we show that there are fundamental differences in how stem cells maintain their developmental potential in embryonic and extraembryonic tissues through miRNAs.

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Stretchy proteins on stretchy substrates: the important elements of integrin-mediated rigidity sensing.

Publication Date: 2010 Aug 17 PMID: 20708583
Authors: Moore, S. W. - Roca-Cusachs, P. - Sheetz, M. P.
Journal: Dev Cell

Matrix and tissue rigidity guides many cellular processes, including the differentiation of stem cells and the migration of cells in health and disease. Cells actively and transiently test rigidity using mechanisms limited by inherent physical parameters that include the strength of extracellular attachments, the pulling capacity on these attachments, and the sensitivity of the mechanotransduction system. Here, we focus on rigidity sensing mediated through the integrin family of extracellular matrix receptors and linked proteins and discuss the evidence supporting these proteins as mechanosensors.

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On the fast track to organizer gene expression.

Publication Date: 2010 Aug 17 PMID: 20708581
Authors: Kimelman, D.
Journal: Dev Cell

Many embryonic species are initially transcriptionally quiescent after fertilization. In this issue of Developmental Cell, Blythe et al. reveal that beta-catenin acts very early in Xenopus development to specifically modify the chromatin of organizer genes, poising them for rapid activation when transcription begins.

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Multiplexing MIM.

Publication Date: 2010 Aug 17 PMID: 20708580
Authors: Kozminski, K. G. - Schafer, D. A.
Journal: Dev Cell

Signaling circuits often coordinate cellular membranes and actin filaments at distinct sites to direct cell behavior. In this issue of Developmental Cell, Bershteyn et al. outline how the molecular scaffold protein, MIM, which bends membranes and binds actin filaments, is at the middle of one such circuit to regulate ciliogenesis.

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Getting one's Fak straight.

Publication Date: 2010 Aug 17 PMID: 20708578
Authors: Evan, G.
Journal: Dev Cell

Focal adhesion kinase (FAK) is a pivotal regulator of integrin signaling and responses to cell adhesive dynamics. In this issue of Developmental Cell, Ashton et al. demonstrate that Fak is critical for intestinal oncogenesis and regeneration after injury but not for day-to-day homeostasis, providing novel insights into intestinal biology and colorectal cancer therapy.

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