Publication Date

2018-05-30

Availability

Embargoed

Embargo Period

2020-05-29

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Neuroscience (Medicine)

Date of Defense

2018-05-03

First Committee Member

Kevin K. Park

Second Committee Member

Sanjoy K. Bhattacharya

Third Committee Member

Nirupa Chaudhari

Fourth Committee Member

Kenneth Muller

Fifth Committee Member

Edmund R. Hollis II

Abstract

Failure of axon regeneration is a major barrier for recovery following neurological injury. Neurons of the mammalian central nervous system (CNS) differ in their ability to regenerate axons. Cell-type specific differences in regenerative capacity are recognized in retinal ganglion cells (RGCs), but the underlying molecular mechanism remains poorly understood. I have shown a previously unappreciated regenerative capacity for melanopsin expressing RGCs (mRGCs) by using transgenic mice that allow reliable surveillance of axonal fates. I identified Thombospondin-1 (Thbs1) as an injury response gene that is unique to RGCs that regenerate. Loss- and gain-of-function studies showed that Thbs1 is important for the regeneration of RGCs following optic nerve crush. Domain deletion experiments showed that the signature thrombospondin type 1 repeats are not required to promote axon regeneration. In contrast, trimerization and the C-terminal domain are necessary for Thbs1 to promote axon regeneration. Together, these results demonstrate the importance of neuronally expressed Thbs1 for the regeneration of adult mammalian RGCs.

Keywords

RGC; melanopsin; axon; regeneration; ganglion; CNS

Available for download on Friday, May 29, 2020

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