Author's School

Graduate School of Arts & Sciences

Author's Department/Program

Biology and Biomedical Sciences: Molecular Genetics and Genomics

Language

English (en)

Date of Award

January 2010

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Chair and Committee

Gregory Longmore

Abstract

The mammalian Ajuba LIM proteins: Ajuba, LIMD1, WTIP) are cytosolic adapter proteins recruited to nascent epithelial adherens junctions, where they are thought to contribute to junctional assembly and/or stability. They also shuttle into the nucleus acting as corepressors of the Snail family of transcriptional repressors, thereby contributing to epithelial mesenchymal transition. As such they have the potential to communicate cell adhesive events with nuclear responses to remodel epithelia. Determining their role(s) in vivo, however, has been challenging due to shared interacting proteins, overlapping tissue expression and functional redundancy in cells. Thus, we turned to the Drosophila model system where a single gene, CG11063 or djub, exists. The generation and analysis of Drosophila containing djub mutant loss-of-function alleles or depleted of dJub by RNAi identify djub as an essential gene required for normal development and a novel regulator of epithelial organ growth as a component of the conserved Hippo pathway, which has been implicated in both tissue size control and cancer development. djub-deficient epithelial tissues were small due to decreased cell numbers resulting from increased apoptosis and decreased proliferation due to the downregulation of DIAP1 and cyclin E, phenocopying tissues deficient for Yorkie: Yki), the downstream target of the Hippo pathway. djub genetically interacts with the Hippo pathway, and genetic epistasis suggests that djub influences wts activity. In mammalian and Drosophila cells, Ajuba LIM proteins/dJub specifically interact with LATS/Wts and WW45/Sav to inhibit phosphorylation of YAP/Yki. This work describes a novel role for the Ajuba LIM proteins as negative regulators of the Hpo signaling pathway.

Comments

Permanent URL: http://dx.doi.org/10.7936/K7V122TP

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