Student Theses and Dissertations

Chan Lek Tan

Date of Award

2013

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

Abstract

MicroRNAs constitute a vital new component of our evolving understanding of regulatory mechanisms that shape cellular gene expression. As ubiquitous regulators of protein translation, microRNAs have a unique regulatory function that is only beginning to be fully described. In addition, their role in the control of gene expression in neurons, which underpins neuronal identity and information processing, has not been fully addressed. In this thesis, I present studies that demonstrate a potent yet previously unknown regulation of neuronal intrinsic excitability by the microRNA miR-128. I show using genetic models that endogenous miR-128 plays a powerful role in dampening the excitability of pyramidal projection neurons in the adult forebrain and demonstrate that the loss of this microRNA alone results in severe motor hyperactivity and fatal epilepsy. By employing genetic tools that permit the interrogation of miR-128-mediated repression and its downstream physiological effects in restricted neuronal populations, I show that miR-128 exerts a sensitive tuning control of target gene expression, intracellular signaling cascades activation and behavioral measures of excitability. The work presented here will help to guide future studies of microRNA function in neurons and other cell types, and reveals a small RNA and its target network as a novel regulatory node with possible implications in animal behavior and human pathology.

Comments

A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy

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