The Role of ZC3H14 in Dendritic Spine Density and Long Term Depression Restricted; Files Only

Abstract

ZC3H14 is an RNA-binding protein that has been linked to non-syndromic autosomal recessive intellectual disability. The function of ZC3H14 is to regulate RNA processing and restrict poly (A) tail length. In non-neuronal cells, ZC3H14 localizes to the nucleus; but data collected from our lab shows in neurons it localizes to dendritic spines. Dendritic spines are tiny membranous protrusions off the dendritic shaft of neurons that receive synaptic inputs and are essential for the brain’s neural networks. These spines contain organelles, signaling proteins and neurotransmitter receptors important for synaptic function and plasticity. Synaptic plasticity includes the strengthening or weakening of these synapses, which is believed to be the cellular basis of learning and memory. Previous studies utilizing a loss-of-function (Zc3h14^{Δex13/Δex13}) model, identified deficits in brain morphology and working memory. We analyzed dendritic spines of hippocampal neurons in Zc3h14^{Δex13/Δex13} mice and found no differences in dendritic spine morphology. We also characterized the ability of ZC3H14 to undergo liquid-liquid phase separation in mammalian cells and identified the intrinsically disordered region and zinc fingers as domains of interest. Preliminary data, from electrophysiological recording of acute hippocampal slices show basal synaptic transmission and long-term potentiation (LTP) are normal, but long-term depression (LTD) is blocked. To determine underlying molecular mechanisms, we researched differences in dendritic spine density with a series of ZC3H14 deletion and truncation mutant constructs in hippocampal neuronal culture. Then, we utilized these constructs to determine which domain of ZC3H14 restores normal LTD in neuronal culture through observing surface AMPA receptor levels. This research provides new insights into the tole of ZC3H14 in synaptic plasticity and neuronal development, improving our understanding of intellectual disability.

Table of Contents

Introduction & Background..............................................................................................................1

Methods..........................................................................................................................................8

Results...........................................................................................................................................13

Discussion......................................................................................................................................19

Future Directions............................................................................................................................22

Figures...........................................................................................................................................23

References......................................................................................................................................30

About this Honors Thesis

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School	Emory College
Department	Neuroscience and Behavioral Biology
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Biology, Neuroscience
Keyword	mRNA processing intellectual disability dendritic spine ZC3H14
Committee Chair / Thesis Advisor	Kenneth Myers, Emory University
Committee Members	Victor Faundez, Emory University Anita Corbett, Emory University

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