Graduation Date

Fall 12-15-2017

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmacology and Experimental Neuroscience

First Advisor

Dr. Jyothi Arikkath

Abstract

The cadherin-catenin complex regulates cell-cell adhesion and signal transduction in epithelial cells. It is becoming increasingly evident that components of the complex regulate various aspects of neuronal architecture and function. δ-catenin is a cytosolic component of the cadherin-catenin complex and is predominantly expressed in the central nervous system. Loss of CTNND2, which encodes δ-catenin, is associated with intellectual disability and mutations in CTNND2 have been identified in autism, suggesting that δ-catenin is a critical component of the molecular machinery underlying neural circuit function. We have previously demonstrated that δ-catenin regulates multiple aspects of synaptic and dendritic development, including dendritic arborization, spine density, architecture and function, consistent with the protein being a key player in regulating neuronal circuit formation and function in the developing brain.

We have identified novel forms of δ-catenin that participate in synaptic regulation. Our data indicate that novel forms of δ-catenin that include either the N-terminal (DcatNT) or C-terminal (DcatCT) regions are expressed in different regions of the brain. These forms are generated via two mechanisms, one of which involves NMDA receptor (NMDAR), Ca2+ and calpain-dependent cleavage while the other mechanism is NMDAR-independent. The DcatCT and NT forms generated in an NMDAR-independent manner are differentially dependent on the lysosome for their generation. Functionally, loss of the domain containing the predicted sites allowing for generation of DcatCT and NT perturbs the density of a subpopulation of dendritic protrusions. Thus, our data provide evidence for a key role for δ-catenin in regulating a subset of dendritic protrusions, and implicate critical functional roles for δ-catenin in neural circuit wiring in the developing hippocampus.

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