Publication Date

2013-09-08

Availability

Embargoed

Embargo Period

2015-09-08

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Neuroscience (Medicine)

Date of Defense

2013-07-30

First Committee Member

Jeffrey Goldberg

Second Committee Member

Akira Chiba

Third Committee Member

Mary Bunge

Fourth Committee Member

Feng Gong

Fifth Committee Member

Leonard Levin

Abstract

A major reason why central nervous system (CNS) trauma and many neurodegenerative diseases demonstrate only limited endogenous repair is the failure of CNS axons to regenerate. Extracellular factors and developmental changes in maturing CNS neurons regulate CNS axon regeneration. The aim of this thesis was to investigate how molecular changes in maturing neurons affect axon growth and regenerative capacity. We found that regulation of subcellular localization of Set-β protein, which is developmentally upregulated in neuronal nuclei, toggles its function between inhibiting and promoting axon growth and regeneration. We also found that developmentally upregulated serotonin receptor 2C suppresses neurite growth and that serotonin receptor 2C knockout mice have elevated excitability in retinal ganglion cells in response to visual stimulation; we also characterized serotonin-synthesizing amacrine cells in the retina. Additionally, we have utilized Next Generation Sequencing (NGS) to identify novel developmentally regulated intrinsic factors in CNS neurons and found multiple new candidates for molecular regulators of axon growth capacity. We also developed an algorithm that utilized NGS data to predict transcription factors that could control neuronal maturation associated with the decline of intrinsic axon regeneration capacity. Finally, towards these same goals, we made progress on NGS analysis of a single retinal ganglion cell, analysis of retinal progenitor subtypes, optimizing a drug screen for differentiation of retinal progenitors, and FACS purification of retinal progenitors. Taken together, these investigations reveal a molecular diversity of developmentally regulated molecules that together regulate a CNS neuron’s intrinsic capacity for axon growth and regeneration, and point towards candidates for novel therapies for CNS trauma and neurodegenerative diseases.

Keywords

Axon growth, CNS, Regeneration, Retinal ganglion cells, Development, Set-beta

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