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Cell-Specific Roles for CASK in the Pathology of Optic Nerve Hypoplasia

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Cell-Specific Roles for CASK in the Pathology of Optic Nerve Hypoplasia Cell-specific roles for CASK in the pathology of Optic Nerve Hypoplasia Alicia Kerr Dissertation submitted to the faculty of the Virginia Polytechnic Institute and State University in partial fulfillment of the requirements for the degree of Doctor of Philosophy In Translational Biology, Medicine, and Health Michael A. Fox (Committee Chair) Gregorio Valdez Konark Mukherjee Harald Sontheimer John Chappell April 25th, 2019 Roanoke, Virginia Keywords: CASK, Optic Nerve Hypoplasia Cell-specific roles for CASK in the pathology of Optic Nerve Hypoplasia Alicia Kerr Abstract 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. ii Cell-specific roles for CASK in the pathology of Optic Nerve Hypoplasia Alicia Kerr General Audience Abstract 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. iii Acknowledgements To my mentor, Dr. Michael Fox, this accomplishment is a testament to your belief in me and there are not enough words to express my gratitude for that. Thank you for all the training about the practice of using the right language to express ideas, the importance of techniques in answering scientific questions, the necessity of patience when you have to repeat an experiment for what feels like the 700th time, and most importantly, the power of a good attitude. To my committee members, and especially Dr. Konark Mukherjee, thank you for your support and guidance throughout this process. To my labmates, Dr. Aboozar Monavarfeshani, Dr. Jianmin Su, Ubadah Sabbagh, Rachana Deven Somaiya, and Gabriela Carrillo, science is a team sport and you all have been the best team. I am a better scientist and a better person because of the mentorship and comradery that you have all given me in your own individual ways. I am lucky to be surrounded by colleagues who care about the human being and not just their scientific output. To my friends who have been so patient with me throughout this process. I am surrounded by an incredible group of women who challenge me to dream bigger and embolden me every step of the way. Thank you, Ashley Alley, Alexandria Pilot, Alyssa Moore, Lexie Mellis and every other person who said “Alicia, wash your hair and let’s go get a drink.” Finally, to my family and especially to my sister Lucinda, thank you for the never ceasing love and encouragement. I am incredibly fortunate to have been raised in a family that has always encouraged creativity and seeking knowledge and puts tremendous value in hard work, traits that my grandparents are incredible representations of. I have dedicated this work to them, Gary and Peggy Kerr and Richard and Penny Sabau. I truly believe that if I have accomplished anything it’s because of the example the four of them set for how to work hard, ask questions, and love and care for people along the way. iv Table of Contents Abstract ...................................................................................................................... ii General audience abstract ....................................................................................... iii Acknowledgments...................................................................................................... iv Table of Contents ....................................................................................................... v List of Figures ............................................................................................................ viii 1. General introduction .............................................................................................. 1 1.1. Optic Nerve Hypoplasia ...................................................................................... 1 1.1.1. Causes of ONH ............................................................................................ 2 1.1.2. CASK identified as risk factor for ONH ........................................................ 5 1.2. Retinofugal circuitry in a murine model ...............................................................6 1.2.1. Mice as models of human retinal diseases .................................................. 6 1.2.2. Retinal cell types and lamination ................................................................. 7 1.2.3. Non-neuronal cell types in the retina ..........................................................13 1.2.4. Dorsal Lateral Geniculate Nucleus of the thalamus ...................................15 1.3. CASK .................................................................................................................17 1.3.1. Role of CASK at the synaptic terminal ........................................................18 1.3.2. CASK mutations in human disease .............................................................20 1.4. Rationale, hypothesis and experimental design .................................................22 References ................................................................................................................37 2. Optic Nerve Hypoplasia is a pervasive subcortical pathology of visual system in neonates .................................................................................................................53 2.1. Abstract ..............................................................................................................54 2.2. Introduction .........................................................................................................55 2.3. Results ................................................................................................................57 2.3.1. Mutations in the CASK gene are associated with ONH .................................57 2.3.2. Heterozygous deletion of CASK in mice produces optic nerve pathology .....58 2.3.3. Axonopathy is present in optic nerves of Cask+/- mice .................................. 59 2.3.4. Retinogeniculate synaptopathy is observed in Cask+/- mice ..........................61 2.3.5. RGC numbers are reduced in Cask+/- mice .................................................. 62 2.3.6. ONH develops postnatally in Cask+/- mice .................................................... 63 2.4. Discussion ................................................. .........................................................64 2.5. Experimental Procedures ................................................................................... 67 v 2.5.1. Identification of a splice mutation in CASK .................................................... 67 2.5.2. Mouse breeding and genotyping ................................................................... 68 2.5.3. Immunohistochemistry ....................................................................................68 2.5.4. Immunoblotting .............................................................................................. 69 2.5.5. Optic nerve samples preparation for toluidine blue staining and transmission electron microscopy (TEM) ...........................................................................................69
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