Optic Nerve Hypoplasia (ONH) is the leading cause of childhood blindness in developed nations and its prevalence has been rising. Yet, we know little about the genetic, molecular, or cellular mechanisms underlying ONH. A previous study described ONH in a cohort of patients with mutations in CASK, an X-linked gene with established roles in neural development and synaptic function. I have demonstrated that heterozygous deletion of CASK in mice (Cask+/-) recapitulates many of the phenotypes observed in patients with CASK mutations, including ONH. This includes reduced optic nerve size, reduced numbers of retinal ganglion cells (RGCs), reduced RGC axonal diameter, and deficits in vision-related tasks. Further analysis on a homozygous partial loss of function variant (Caskfl/fl) also displayed ONH with reduced numbers of RGCs. In order to understand the mechanisms underlying CASK-associated ONH, I explored whether RGCs, the projection neurons of the retina and the cells whose axons comprise the optic nerve, generate CASK. Indeed, mRNA analysis revealed expression of CASK by a large cohort of RGCs. In order to assess whether loss of CASK from a majority of RGCs leads to ONH, I crossed a conditional allele of CASK (CASKfl/fl) with transgenic mice that express Cre Recombinase (Cre) in RGCs. Deletion of CASK from RGCs did not further alter ONH size nor RGC survival. These results demonstrate that loss of CASK signaling in this discrete neuronal populations is not sufficient to lead to further disruption in the assembly of the subcortical visual circuit, suggesting a non-cell autonomous mechanism for loss of CASK in ONH. / Doctor of Philosophy / The connection between the eye and the brain is crucial for successful vision. Impairment of this connection by either loss of the retinal neurons that project axons to the brain or damage to the nerve (optic nerve) lead to blindness. This occurs in a disease called Optic Nerve Hypoplasia (ONH), which is the leading cause of childhood blindness in developed countries. Discovering the risk factors associated with this disease and mechanisms underlying the disease can help us build tools to treat and repair the optic nerve. Previously, mutations in the CASK gene were found in patients with ONH. Here, I developed a mouse model of CASK mutations to phenocopy the human patients, and used this model to explore the development of ONH. For example, with this mouse model I described for the first time, the timeline of disease progression. Surprisingly, I also showed that loss of CASK specifically from the neurons whose axons generate the optic nerve did not lead to ONH, suggesting that ONH may develop from a failure of a network of cells, rather than just one population of cells.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/101514 |
| Date | 25 June 2019 |
| Creators | Kerr, Alicia Marie |
| Contributors | Graduate School, Fox, Michael A., Chappell, John C., Mukherjee, Konark, Valdez, Gregorio, Sontheimer, Harald |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Detected Language | English |
| Type | Dissertation |
| Format | ETD, application/pdf |
| Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
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