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Non-canonical Wnt signaling and vertebrate gastrulation

by
Wei Liu
BS, 2000
Wuhan University
China

Thesis Advisor: Raymond Habas, PhD
Graduate Program of Biochemistry & Molecular Biology

CABM 010

Monday, September 21, 2009
2:00 pm


Abstract

The Wnt signaling pathway play crucial roles during embryogenesis and one aspect of Wnt signaling involves dramatic changes to the cellular actin cytoskeleton to mediate motility. How Wnt signaling proceeds from the plasma membrane to regulate changes to the actin cytoskeleton remains poorly understood. Our lab has previously identified the Formin homology protein, Daam1, as a central factor required for Wnt-induced cytoskeletal changes but how Daam1 accomplishes this is not known.

In this dissertation, we report a novel mechanism for the activation of Daam1 and characterize two effectors for Daam1. The Wnt induced Dvl binding to the DAD domain of Daam1 disrupt the intramolecular interaction that locked Daam1 in the inactive state. The activated Daam1 in turn induce the activation of RhoA GTPase. Our studies uncover the role of Dvl as an important factor that activates Daam1.

In search of downstream effectors for Daam1, we have isolated and characterized “missing in metastasis”, known as MIM, and Profilin1 as binding partners for Daam1. We further show MIM is required for anterior neural fold closure while Profilin1 is required for blastopore closure during development. Taken together, we propose that MIM and Proflin1 are major factors downstream of Daam1 in the non-canonical Wnt pathway and upon Wnt signaling, Dvl binds to Daam1 and recruits MIM and Profilin into the Dvl/Daam1 complex. The recruitment of MIM and Profilin1 can directly exert changes to the actin-cytoskeleton, cell polarity and motility and in turn affect the interrelationships between cell polarity, cellular morphogenesis and cell fate determination.


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