63 research outputs found

    Atypical Cadherin Dachsous Regulates The Cytoskeleton And Gastrulation Movements During Zebrafish Development

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    Dachsous (Dchs), an evolutionarily conserved atypical cadherin, regulates planar cell polarity, tissue size, and cell adhesion in Drosophila. However, its functions in vertebrates are just beginning to be elucidated. Inactivating one of two murine homologs, Dchs1, leads to multi-organ defects and postnatal lethality. Recent studies in humans suggest that mutations in DCHS1 cause pleiotropic Van Maldergem syndrome. My thesis work focuses on the functional characterization of zebrafish dchs1b and dchs2 genes. Mutations in dchs1b and dchs2 genes affect several aspects of embryogenesis, including gastrulation. Unexpectedly, dchs1b is also essential for the earliest vertebrate developmental stage, egg activation. We show that maternally contributed dchs1b coordinates cytoskeleton dependent processes including cortical granule exocytosis (GCE), cytoplasmic segregation, cell divisions, and maternal mRNA translocation in transcriptionally silent early embryos. Later, maternal zygotic (MZ) dchs1b mutants exhibit altered expression of several genes expressed in the dorsal organizer and mesendoderm, due to impaired transport of a dorsal determinant and Nodal signaling. Mechanistically, aspects of the MZdchs1b phenotype can be explained by defects in either actin and/or microtubule networks, which both appear aberrantly bundled in mutants. Accordingly, disruption of actin cytoskeleton in wild-type embryos phenocopied MZdchs1b mutant defects in cytoplasmic segregation and CGE. Whereas, interfering with microtubules in wild-type embryos impaired dorsal organizer and mesodermal gene expression without perceptible earlier phenotypes. During gastrulation, both MZdchs1b and MZdchs2 mutants manifest defects in morphogenic movements: delayed epiboly in mutants is caused in part by defects in actin and microtubule cytoskeleton and adhesion defects, which is independent of planar cell polarity pathway; and cell polarity that drives convergence and extension, which is under planar cell polarity pathway regulation. My work establishes novel roles for vertebrate Dchs in actin and microtubule cytoskeletons regulation in an unanticipated single cell context of the early zygote and conservation of function for Dchs in regulation of planar cell polarity that could contribute to the pleiotropic defects caused by mutations in mammalian Dchs homologs

    Optically and Electrically assisted Micro-Indentation

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    Local retinoic acid signaling directs emergence of the extraocular muscle functional unit

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    Coordinated development of muscles, tendons, and their attachment sites ensures emergence of functional musculoskeletal units that are adapted to diverse anatomical demands among different species. How these different tissues are patterned and functionally assembled during embryogenesis is poorly understood. Here, we investigated the morphogenesis of extraocular muscles (EOMs), an evolutionary conserved cranial muscle group that is crucial for the coordinated movement of the eyeballs and for visual acuity. By means of lineage analysis, we redefined the cellular origins of periocular connective tissues interacting with the EOMs, which do not arise exclusively from neural crest mesenchyme as previously thought. Using 3D imaging approaches, we established an integrative blueprint for the EOM functional unit. By doing so, we identified a developmental time window in which individual EOMs emerge from a unique muscle anlage and establish insertions in the sclera, which sets these muscles apart from classical muscle-to-bone type of insertions. Further, we demonstrate that the eyeballs are a source of diffusible all-trans retinoic acid (ATRA) that allow their targeting by the EOMs in a temporal and dose-dependent manner. Using genetically modified mice and inhibitor treatments, we find that endogenous local variations in the concentration of retinoids contribute to the establishment of tendon condensations and attachment sites that precede the initiation of muscle patterning. Collectively, our results highlight how global and site-specific programs are deployed for the assembly of muscle functional units with precise definition of muscle shapes and topographical wiring of their tendon attachments

    내재적 VEGF 억제자인 KAI1의 혈관신생 조절에 관한 연구

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    학위논문 (박사)-- 서울대학교 대학원 : 의과대학 의과학과, 2018. 8. 김효수.Angiogenesis represents new blood-vessel formation controlled by numerous factors. VEGF, the most potent pro-angiogenic factor, is commonly targeted in cancer therapy. However, little is known about endogenous VEGF inhibitors and their control. Here, CD82/KAI1 expressed on pericytes (PCs) acts as an endogenous anti-angiogenic factor. Through transcriptome and functional analysis, I revealed that leukemia inhibitory factor (LIF) is an anti-angiogenic effector molecule of KAI1 through KAI1-Src-p53 axis. Furthermore, KAI1 was shown to bind VEGF and PDGF-BB, preventing VEGFR/PDGFR signalling and tube formation by endothelial cells. In the therapeutic aspect, KAI1-overexpressing pericytes or recombinant KAI1 protein inhibited angiogenesis and cancer cell growth. Taken together, I demonstrated that KAI1 is a key regulator of angiogenesis by interacting with the angiogenic niche, and identified novel molecular mechanisms underlying anti-VEGF/PDGF therapy, which may help develop new anti-cancer strategies.Abstract 1 Contents 3 List of tables and figures 4 List of abbreviations 5 Title [An endogenous VEGF inhibitor, KAI1, is a master switch of angiogenesis] 6 Introduction 7 Materials and Methods 9 Results 27 Discussion 61 References 65 Abstract in Korean 68Docto

    The eye as a miRror:targeting microRNAs in ocular pathologies

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    VEGF-mediated vascular functions in health and disease

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    Axon patterning in the mouse retinofugal pathway.

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    Leung Kin Mei.Thesis (M.Phil.)--Chinese University of Hong Kong, 2002.Includes bibliographical references (leaves 106-125).Abstracts in English and Chinese.Chapter CHAPTER 1 --- GENERAL INTRODUCTION --- p.1-11Chapter CHAPTER 2 --- ENZYMATIC REMOVAL OF CHONDROITIN SULFATES ABOLISHES THE AGE-RELATED ORDER IN THE OPTIC TRACT OF MOUSE EMBRYOSINTRODUCTION --- p.12-13MATERIALS AND METHODS --- p.13-18RESULTS --- p.18-24DISCUSSION --- p.24-29FIGURES --- p.30-39Chapter CHAPTER 3 --- EXPRESSION OF PHOSPHACAN AND NEUROCAN IN THE DEVELOPING MOUSE RETINOFUGAL PATHWAYINTRODUCTION --- p.40-42MATERIALS AND METHODS --- p.42-43RESULTS --- p.44-49DISCUSSION --- p.49-55FIGURES --- p.56-61Chapter CHAPTER 4 --- HEPARAN SULFATE PROTEOGLYCAN EXPRESSION IN THE OPTIC CHIASM OF MOUSE EMBRYOSINTRODUCTION --- p.62-63MATERIALS AND METHODS --- p.63-65RESULTS --- p.66-70DISCUSSION --- p.70-76FIGURES --- p.77-82Chapter CHAPTER 5 --- EXPRESSION OF NEURAL CELL ADHESION MOLECULES IN THE CHIASM OF MOUSE EMBRYOSINTRODUCTION --- p.83-85MATERIALS AND METHODS --- p.85-88RESULTS --- p.88-92DISCUSSION --- p.92.95FIGURES --- p.96-102Chapter CHAPTER 6 --- GERNEAL CONCLUSION --- p.103-105REFERENCES --- p.106-12

    Axon patterning in the mouse retinofugal pathway.

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    Leung Kin Mei.Thesis (M.Phil.)--Chinese University of Hong Kong, 2002.Includes bibliographical references (leaves 106-125).Abstracts in English and Chinese.Chapter CHAPTER 1 --- GENERAL INTRODUCTION --- p.1-11Chapter CHAPTER 2 --- ENZYMATIC REMOVAL OF CHONDROITIN SULFATES ABOLISHES THE AGE-RELATED ORDER IN THE OPTIC TRACT OF MOUSE EMBRYOSINTRODUCTION --- p.12-13MATERIALS AND METHODS --- p.13-18RESULTS --- p.18-24DISCUSSION --- p.24-29FIGURES --- p.30-39Chapter CHAPTER 3 --- EXPRESSION OF PHOSPHACAN AND NEUROCAN IN THE DEVELOPING MOUSE RETINOFUGAL PATHWAYINTRODUCTION --- p.40-42MATERIALS AND METHODS --- p.42-43RESULTS --- p.44-49DISCUSSION --- p.49-55FIGURES --- p.56-61Chapter CHAPTER 4 --- HEPARAN SULFATE PROTEOGLYCAN EXPRESSION IN THE OPTIC CHIASM OF MOUSE EMBRYOSINTRODUCTION --- p.62-63MATERIALS AND METHODS --- p.63-65RESULTS --- p.66-70DISCUSSION --- p.70-76FIGURES --- p.77-82Chapter CHAPTER 5 --- EXPRESSION OF NEURAL CELL ADHESION MOLECULES IN THE CHIASM OF MOUSE EMBRYOSINTRODUCTION --- p.83-85MATERIALS AND METHODS --- p.85-88RESULTS --- p.88-92DISCUSSION --- p.92.95FIGURES --- p.96-102Chapter CHAPTER 6 --- GERNEAL CONCLUSION --- p.103-105REFERENCES --- p.106-12
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