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

Vertebrate gastrulation is a fundamental morphogenetic process during which germ layers are formed, patterned and shaped into a body plan with organ rudiments. Among the conserved gastrulation movements, convergence and extension (C&E) occur concurrently to narrow the germ layers mediolaterally and elongate them along the anteroposterior embryonic axis. C&E are largely driven by cell migration and cell intercalation, while cell proliferation has been considered dispensable and even incompatible with gastrulation movements and morphogenesis. Signal transducer and activator of transcription 3 (Stat3) has been implicated by antisense morpholino loss-of-function study in regulation of zebrafish C&E movements in part by promoting non cell-autonomously convergence movements and the Wnt/Planar Cell Polarity (Wnt/PCP) signaling-dependent mediolateral (ML) cell polarity that underlies polarized gastrulation cell behaviors. In this thesis work, I showed that TALEN-based genetic disruption of both maternal and zygotic stat3 function led to proliferation and axis extension defects without affecting convergence movement or planar cell polarity. Rather, my studies posit an alternative model of Stat3 function during early embryogenesis, whereby Stat3 promotes extension of embryonic tissues via Cdc25a-dependent cell proliferation. These results clarify the role of Stat3 function in gastrulation and providing evidence that cell proliferation plays a small but significant role in tissue extension during gastrulation. Despite decreased early cell proliferation and extension movements during gastrulation, stat3–deficient zebrafish mutants complete gastrulation, contrasting the severe C&E defects induced by stat3 morpholino. I therefore used stat3 morpholino as a tool and uncovered several novel regulators of C&E by gene expression profiling. Among those, Fam132a, a conserved secreted peptide, regulates morphogenesis of the prechordal and chorda axial mesoderm likely in a Wnt/PCP-independent manner. In particular, Fam132a modulates the collective anterior migration of the prechordal plate progenitors by limiting cell contact, required for their effective directed migration. Together, my work has established a conserved role of Stat3 in regulation of cell proliferation, and uncovered novel regulators of zebrafish gastrulation. In addition, stat3-deficient juveniles develop scoliosis and excessive inflammation phenotypes, affording a genetic model of STAT3-associated human diseases.

Language

English (en)

Chair and Committee

Lilianna Solnica-Krezel

Committee Members

Stephen L. Johnson, Christina A. Gurnett, Craig Micchelli, ,

Comments

Permanent URL: https://doi.org/10.7936/K7QR4V97

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