Congress Abstracts - Society for Developmental Biology

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completed their constriction and have begun to translocate towards the interior of the embryo, the lateral and dorsal cells begin to move and change their shapes. We will present the dynamics of their behaviour relative to the mesoderm in wildtype, mutant and experimentally manipulated embryos. Program/Abstract # 9 Functionally co-operating T-box transcription factors define neuro-mesodermal bipotency during vertebrate axial elongation George Gentsch, Nick Owens, Stephen Martin, Michael Gilchrist, James Smith (NIMR, UK) The development of effective cell replacement therapies requires detailed knowledge of how embryonic stem cells form primary tissues such as mesoderm or neurectoderm in vivo. Recent work indicates that the caudal region of the vertebrate embryo contains stem cells that can give rise to both mesodermal and neural derivatives. By combining genome-wide chromatin profiling and gain- and loss-of-function experiments in vivo as well as quantification of DNA binding dynamics in vitro, we provide here unprecedented mechanistic insights into T-box transcription factor-mediated cell fate switches to form correctly proportioned neural and mesodermal tissues along the rostro-caudal axis of the frog embryo. The T-box transcription factors Eomesodermin, VegT and Brachyury recruit RNA polymerase II and signalling mediators to run the transcriptional machinery for mesodermal cell fate acquisition. Consequently, their combined loss eliminates the mesodermal potential inherent to neuro-mesodermal stem cells and causes the embryo to develop a single oversized neural tube without any mesodermal derivatives including skeletal muscle, heart and pronephros. Program/Abstract # 10 Transcriptional coding of muscle identity in Drosophila Alain Vincent, Hadi Boukhatmi, Laurence Dubois, Mathilde De Taffin, Jean-Louis Frendo, Laetitia Bataillé, Michèle Crozatier (CNRS - Univ. de Toulouse, France) The Drosophila larval musculature is composed of a stereotyped array of morphologically distinct muscles. Each skeletal muscle is seeded by a founder myoblast (FC) issued from the asymmetric division of a progenitor cell (PC) specified at a fixed position within the somatic mesoderm. It has been long proposed that each muscle identity - orientation, size, shape, skeletal attachment sites - could reflect unique combinations of “identity” transcription factors (iTFs) expressed by each FC. However, our understanding of this process is far from complete. By studying the Collier/EBF and Tup/Islet1 iTFs, we have recently shown that a key step is the segmentspecific activation/cross regulation of iTFs, which occurs in each PC and integrates both positional and temporal cues. We have now undertaken genome-wide genetic and molecular screens in order to obtain a global view of muscle identity specification, focusing on dorsal and dorso-lateral muscles, including the alary muscles which “support” the heart. The results indicate a complex network of iTF regulation and establish new parallels between specification of pharyngeal muscles in chordates and dorsal muscles in Drosophila. Program/Abstract # 11 Beta-catenin expression in Wolffian ducts is essential for Müllerian duct development during female sexual differentiation Dibyendu Dutta, Thomas Marose, Calli Merkel, Thomas Carroll (UT Southwestern Med. Ctr., USA) During female sexual differentiation in mammals, the Wolffian duct (WD) (that gives rise to male reproductive tracts) is degraded while the Müllerian duct (MD) differentiates into the female reproductive tract (oviduct, uterus and vagina). Although a great deal is known about the genetic regulation of sex determination, relatively little is known about the molecules that regulate the differentiation of the sex organs. We deleted beta-catenin from the mouse WD using the HoxB7Cre deleter strain and a floxed allele of beta-catenin. Mutant females showed a partial sex reversal where the WD was maintained while the MD did not form. Since HoxB7 is also expressed in the neural crest, we used alternative deleter strains including Pax2Cre (active in the WD) and Wnt1Cre (active in the neural crest) to determine in which cell type beta-catenin was required. Deletion of beta-catenin with Pax2Cre (but not Wnt1Cre) recapitulated the partial sex reversal phenotype suggesting beta-catenin was required in the WDs. Somewhat surprisingly, we found that the partial sex reversal was not due to inappropriate androgen production or masculinization of ovaries. Instead, it appears to be caused by premature differentiation of the WD rendering it impervious to the normal apoptosis program induced in females. Further, the differentiated ducts fail to express factors (including Wnt9b) necessary for MD migration. Thus, we have found that beta-catenin regulates reproductive tract differentiation in an androgen independent manner. Program/Abstract # 12 Fat-PCP regulation of neuronal migration Philippa H. Francis-West, Sana Zakaria (King’s College London, UK); Yaopan Mao (Rutgers, USA); Anna Kuta, Robert Hindges, Sarah Guthrie (King’s College London, UK); Kenneth Irvine (Rutgers, USA) Planar cell polarity (PCP) is classically defined as the polarisation of tissue structures perpendicular to the apical-basal axis. In Drosophila and vertebrates, PCP is controlled by the Frizzled-PCP and Fat-PCP pathways. However, evidence for conservation of the Fat-PCP pathway in vertebrates is limited. During development, Facial-branchiomotor neurons (FBN) undergo tangential caudal and medio-lateral migrations within the plane of the neuroepithelium, and are a model system for the study of PCP. Previous studies have shown a critical role for Fz-PCP during caudal migration. We have examined the role of Fat-PCP signalling during FBN migration by analysing mouse mutant for Fat4 and Dchs1, the vertebrate homologues of Drosophila Fat and Ds respectively. We show that in Fat4 and Dchs1 mouse mutants, FBN fail to undergo the medio-lateral migration and are not polarised appropriately. We also show that Dchs1 and Fat4 are expressed in opposing gradients along the medio-lateral axis suggesting that as in Drosophila, gradients of Fat 4
activity may determine the orientation of tissue structures. Indeed, chimeric analysis, which would disrupt these gradients, affects medio-lateral migration. This clearly demonstrates that Fat-PCP signalling is conserved in vertebrates and also implicates for the first time gradients of Fat4/Dchs1 activity in the establishment of PCP. This data also define Fat-PCP as novel neuronal guidance cues and show a novel system where Fz-PCP and Fat-PCP determine the polarisation of tissue structures along orthogonal axes. Program/Abstract # 13 Systematic discovery of novel cilia and ciliopathy genes through functional genomics in the zebrafish Semil P. Choksi, Deepak Babu (IMCB, Singapore); Malgorzata Szczepaniak, Rim Hjeij (Univ. Hosp. Muenster, Germany); Doreen Lau, Xianwen Yu (IMCB, Singapore); Petra Pennekamp, Claudius Werner, Niki T. Loges (Univ. Hosp. Muenster, Germany); Karsten Häffner (Univ. Hosp. Freiburg, Germany); Shunzhen Chen, Kangli Noel Wong (IMCB, Singapore); Gerard Dougherty (Univ. Hosp. Muenster, Germany); Ronald Roepman (Radboud Univ., Netherlands); Heymut Omran (Univ. Hosp. Muenster, Germany); Sudipto Roy (IMCB, Singapore) Cilia are microtubule-based hair-like organelles that play many important roles in animal development and physiology. Ciliary dysfunction is implicated in a rapidly expanding spectrum of diseases, the ciliopathies. Primary ciliary dyskinesia (PCD), one of the most prevalent ciliopathies, is a genetically heterogeneous disease that arises from faulty motile cilia. As causative mutations in relatively few genes have been described, we sought to systematically identify new ciliopathy genes using functional genomics coupled with rapid phenotype screening in the zebrafish embryo. With this approach, we identified hundreds of cilia genes, a majority of which have never been associated with cilia before. We selected 50 genes at random and, remarkably, found that more than 60% are required for ciliary differentiation or function. In addition, we find that proteins encoded by 14 of the genes localize to motile cilia. By sequencing a cohort of PCD patients for mutations in these genes, we show that several of the novel candidates, including ZBBX and MNS1, are mutated in patients suffering from PCD. We find that these genes affect ciliary motility by disrupting the nexin-dynein regulatory complex and the outer dynein arm assembly, respectively. This large collection of functionally-validated motile cilia genes will be invaluable for the study of ciliary biology, and in the identification of new mutations causing ciliopathies like PCD. Program/Abstract # 14 Sox10 regulates enteric neural crest cell migration in the developing gut Mai Har Sham, Carly Leung, Mei Zhang, Hon Man Sit (U Hong Kong, China) Sox10 is a HMG-domain containing transcription factor which plays important roles in neural crest cell survival and differentiation. Mutations of Sox10 have been identified in patients with Waardenburg-Hirschsprung syndrome, who suffer from deafness, pigmentation defects and intestinal aganglionosis. Enteric neural crest cells (ENCCs) with Sox10 mutation undergo premature differentiation and fail to colonize the distal hindgut. It is unclear, however, whether Sox10 plays a role in the migration of ENCCs. To visualize the migration behaviour of mutant ENCCs, we generated a Sox10 NGFP mouse model where EGFP is fused to the N-terminal domain of Sox10. Using time-lapse imaging, we found that ENCCs in Sox10 NGFP/+ mutants displays lower migration speed and altered trajectories compared to normal controls. This behaviour was cell-autonomous, as shown by organotypic grafting of Sox10 NGFP/+ gut segments onto control guts and vice versa. ENCCs encounter different extracellular matrix (ECM) molecules along the developing gut. We performed gut explant culture on various ECM and found that Sox10 NGFP/+ ENCCs tend to form aggregates, particularly on fibronectin. Time-lapse imaging of single cells in gut explant culture indicated that the tightly-packed Sox10 mutant cells failed to exhibit contact inhibition of locomotion. We determined the expression of adhesion molecule families by qPCR analysis, and found integrin expression unaffected while L1-cam and selected cadherins were altered, suggesting that Sox10 mutation affects cell adhesion properties of ENCCs. Our findings identify a de novo role of Sox10 in regulating the migration behaviour of ENCCs, which has important implications for the treatment of Hirschsprung disease. Program/Abstract # 15 Epigenetic Regulation of Intestinal Inflammation in Zebrafish Lindsay Marjoram, Michel Bagnat (Duke, USA) Our lab recently performed a forward genetic screen in zebrafish and identified mutants with perturbed epithelial integrity in the intestine. One of these mutants, aa51.3, shows excess epithelial cell shedding and apoptosis in the intestine. This phenotype is accompanied by loss of epithelial folds and nonpolarized distribution of cadherin. The observed defects are consistent with an inflammatory bowel disease-like phenotype. Tumor necrosis factor, a pro-inflammatory cytokine, plays a prominent role in inflammation and its overexpression is correlated with inflammatory bowel disease and defects in intestinal epithelial integrity. To monitor inflammation, we generated an inflammation-responsive tumor necrosis factor transgenic line, TgBAC(tnfa:GFP). In aa51.3 mutants, TgBAC(tnfa:GFP) is dramatically upregulated along the entire length of the intestine. Exome sequencing followed by positional cloning identified a causative splice-site mutation in the gene encoding Ubiquitin-like, Containing PHD and Ring Finger Domains 1 (Uhrf1), which plays a fundamental role in epigenetic regulation of gene expression by promoting DNA maintenance methylation. Expression of uhrf1 is spatially restricted to the eye, liver and gut in five day post-fertilization larvae, a stage when we observe elevated intestinal tnfa expression. Our data suggest that loss of maintenance methylation in the tnfa promoter leads to elevated expression of tnfa in the intestine, which subsequently promotes the observed intestinal defects in aa51.3 mutants. This research will provide insights into how changes in methylation may promote the development of inflammatory diseases and may uncover new therapeutic targets. 5
Page 1 and 2: International Society of Developmen
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Page 7 and 8: Developmental cell signaling pathwa
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Page 11 and 12: functions by the recruitment of add
Page 13 and 14: function validated with explant stu
Page 15 and 16: Program/Abstract # 48 Modeling regu
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Page 19 and 20: morphologies. Our analyses not only
Page 21 and 22: junctional proteins (RPE patterning
Page 23 and 24: Program/Abstract # 78 In vivo recep
Page 25 and 26: Program/Abstract # 85 Guts and gast
Page 27 and 28: Program/Abstract # 92 The C. elegan
Page 29 and 30: Program/Abstract # 98 A gradient of
Page 31 and 32: Program/Abstract # 106 Developing a
Page 33 and 34: NSCs, but not in neurons, bind not
Page 35 and 36: abnormalities in the development of
Page 37 and 38: Tbx4 and contributes to Tbx4 repres
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Page 43 and 44: understanding the mechanisms that u
Page 45 and 46: Program/Abstract # 156 Systematic I
Page 47 and 48: Program/Abstract # 163 Size regulat
Page 49 and 50: TACC3 was localized around the DNA
Page 51 and 52: Penaeid shrimp represent an importa
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show that cell polarity is disrupte
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process. However, a clear mechanist
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Zhang, Haoran; Wong, Elaine Yee-man
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condition. Kanyon embryos have a mi
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Program/Abstract # 218 Lfng regulat
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works in concert with basal cues fr
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medaka genome. These miRs are encod
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facilitan cambio en patrón morfoge
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coordinately regulate the expressio
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downstream asymmetric signals. The
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viability and morphology of over 20
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owser. The genomic differences obse
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evolutionary analysis to study the
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teleostei. Our data evidenced that
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ontogeny. The typical condition for
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examples whose Shh expression requi
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insights into the ancestral role of
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Program/Abstract # 308 Mechanistic
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Patients with Joubert Syndrome and
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Program/Abstract # 323 Drosophila g
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signalling during gut and enteric n
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normally form, hence producing prox
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survival in Shh mutant embryos foll
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conserved in amniotes other than ch
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maturation and function. We strive
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Urness, Lisa D; Bleyl, Steven B (Un
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development is already unknown. Emb
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in A-P and P-D patterning by establ
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perturbed in arco piccolo mutants w
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Hoxb7-Cre line, leads to multiple u
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differentiation from common progeni
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investigate this issue, we used tar
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stem cell‐like characteristics. H
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diminished. Interestingly, we found
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y invading osteoblasts. Quite diffe
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coimmunoprecipitation experiments d
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cells and sub-cellular endosomal co
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accumulation is decreased. This wor
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Sex determination in vertebrates de
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Program/Abstract # 462 Retinaldehyd
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Program/Abstract # 469 Search for n
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growth factors used to keep them al
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it is still required to promote mig
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on the outside of small clear vesic
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Program/Abstract # 497 mef2ca contr
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were colocalized along the epidermi
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neural tube morphogenesis, is conse
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Hypoxia-inducible factors (HIFs) ar
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To address this issue, we have take
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Program/Abstract # 530 The MADS pro
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Better understanding of the underly
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NPCs blunted proliferation in the S
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Program/Abstract # 551 Evolutionari
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group is interested in inferring an
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Program/Abstract # 564 Withdrawn Pr
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Program/Abstract # 573 Fluoride ind
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oligodendrocytes of the central ner
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cycle, no changes were observed in
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have begun to document the targets
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Congress Abstracts - Society for Developmental Biology

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