Date of Award

Summer 8-15-2015

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Developmental, Regenerative, & Stem Cell Biology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

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.

Language

English (en)

Chair and Committee

Lilianna Solnica-Krezel

Committee Members

James Skeath, Gregory Longmore, John Cooper, Kristen Kroll, Kelly Monk

Comments

Permanent URL: https://doi.org/10.7936/K7862DQX

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