Author ORCID Identifier

0000-0003-0487-4912

Date of Graduation

12-2019

Document Type

Dissertation (PhD)

Program Affiliation

Neuroscience

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Pierre D. McCrea, Ph.D.

Committee Member

Darren Boehning, Ph.D.

Committee Member

Eric Swindell, Ph.D.

Committee Member

M. Neal Waxham, Ph.D.

Committee Member

Jack Waymire, Ph.D.

Abstract

The formation of neuronal networks in the brain is tightly regulated, and dependent on the morphology of dendrites, the branch-like signal-receiving structures extending from neurons. Disruptions in dendrite development, or dendritogenesis, can lead to the atypical neuronal connectivity associated with multiple neurodevelopmental diseases. My research addresses molecular processes that underlie dendritogenesis via analysis of a pair of novel interactions involving the protein delta-catenin.

In neurons, delta-catenin localizes to dendrites and synapses, where it functions in their development and maintenance. Structurally, delta-catenin possesses a central Armadillo domain and a C-terminal PDZ-binding motif. This motif associates with PDZ domain-containing proteins, and is crucial for the neuronal functions of delta-catenin. My research has revealed two novel interactions between delta-catenin and the PDZ domain-containing proteins Magi1 and Pdlim5.

Through the use of cell-lines and primary neuronal cultures, I have begun to reveal the functions of these proteins in dendrite development. My findings suggest that delta-catenin is required for the extension of dendrites, and induces dendritic branching during neuronal development. My work has also shown that Magi1 promotes dendrite extension, but not dendritic branching. Conversely, Pdlim5 appears to function in restricting dendrite growth, while simultaneously promoting dendritic branching. This presented me with the perplexing thought that either of these two proteins, with seemingly opposing dendritic roles, can each bind the PDZ-binding motif of delta-catenin.

Further analysis of these proteins revealed a potential “phospho-switch” mechanism in the function of delta-catenin. Specifically, I found a pair of critical serine residues within delta-catenin (S1245 and S1242), that enable it to bind Magi1 (when unphosphorylated) or Pdlim5 (when phosphorylated). Expressing delta-catenin mutants, which mimic the unphosphorylated versus phosphorylated state, shifted its function between promoting dendrite elongation or branching, respectively. Looking upstream of delta-catenin phosphorylation, my findings implicate the glutamate receptor mGluR5, which has extensive roles in dendrite development, in this pathway. Lastly, my investigation suggested that Rho-family GTPases lie downstream of these delta-catenin complexes, thereby linking them to cytoskeletal regulators with established roles in dendritogenesis.

Overall, my research furthers our understanding of the mechanisms underlying dendrite development, and may help provide insight into the progression of several neurodevelopmental disorders.

Keywords

Dendrites, Phosphorylation, Glutamate, Catenin, PDZ, Development, Neuron, Cell Signaling

Available for download on Friday, December 04, 2020

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