All ETDs from UAB

Advisory Committee Chair

Jianbo Wang

Advisory Committee Members

Chenbei Chang

Rosa Serra

Alexa Mattheyses

Bingdong Sha

Document Type

Dissertation

Date of Award

2023

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

A broad spectrum of human birth defects arise from the disruption of morphogenesis, the critical process through which tissues and organs acquire their proper shape. Convergent extension (CE) is a universal morphogenetic engine that promotes polarized extension of diverse tissues and organs by regulating directional cell behavior, such as oriented cell intercalation. In vertebrates, CE is regulated by non-canonical Wnt/Planar Cell Polarity (PCP) pathway, an ancient signaling pathway that was originally discovered to coordinate the cellular polarity in the plane of the epithelium. Non-canonical Wnt/PCP signaling shares the Frizzled (Fz) receptor and cytoplasmic signal transducer Dishevelled (Dvl) with the canonical Wnt pathway, but also involves a set of distinct core proteins such as the tetraspanin protein Van gogh (Vang/Vangl) and Dishevelled-associated activator of morphogenesis 1 (Daam1). However, the mechanism of non-canonical Wnt signaling in mesodermal cells during CE has not been well elucidated. Utilizing Xenopus laevis, a well-established model for CE, our lab previously found that Vangl is required for plasma membrane recruitment of Dvl, a pre-requisite of non-canonical Wnt signaling. Sustained binding of Dvl to Vangl, however, inhibits Dvl interaction with Fz, thereby preventing signaling activation. To investigate how Dvl binding to Vangl or Fz may be regulated, I studied DACT1, a cytoplasmic scaffolding protein that interacts with both, Dvl and Vangl. My data revealed that DACT1 synergizes with Dvl2 but antagonizes Vangl2 function during CE, suggesting a clear role in non-canonical Wnt signaling during CE. Additionally, DACT1 disengages Dvl from Vangl, though not via competitive binding at Vangl2, but by inducing Dvl oligomerization. Intriguingly, DACT1-induced Dvl oligomers detach from Vangl2 but interact with Fz7 to form signalosome-like structures at the plasma membrane. Furthermore, in response to a non-canonical Wnt ligand, Wnt11, DACT1 promotes Dvl clustering in membrane patches at the Fz receptor. My results reveal the significant role of DACT1-induced Dvl2 oligomerization in regulating several aspects of non-canonical Wnt signaling during CE: 1) Dvl2 binding partner switch, 2) signalosome formation at Fz, and 3) clustering in response to a Wnt11 ligand. Taken together, my results show that DACT1 plays a novel role in regulating non-canonical Wnt signaling by inducing Dvl oligomerization.

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