UC Santa Cruz

Neurons in the mammalian central nervous system must be maintained throughout the lifetime of an organism because they are unable to regenerate. Retinal ganglion cells (RGCs) are the projection neurons of the retina that project directly to and form connections with the brain. Injury and disease can damage RGC axons, ultimately leading to RGC death and resulting in blindness. Learning how to protect these cells from dying and how to regenerate them after loss remain critical goals of vision neuroscientists; these endeavors aim to prevent blindness in those at risk and to restore vision in individuals already blind or visually impaired. Transcription factors regulate the development, maintenance, and survival of neurons. In this dissertation, I explore the roles of two transcription factors, Tbr2 and Isl2, in these important processes. My lab has previously demonstrated that Tbr2 is required during development for the formation and survival of intrinsically photosensitive RGCs (ipRGCs), a unique class of RGCs that are resilient to injury. The persistent expression of Tbr2 in a subset of adult RGCs, including all ipRGCs, led to the hypothesis that it is required for their maintenance and survival. In this dissertation, I establish that Tbr2 is indeed necessary for maintaining the defining aspect of ipRGC identity–the expression of the photopigment melanopsin, which enables them to directly respond to light. However, Tbr2 is not essential for the survival of adult ipRGCs. Additionally, I show that after optic nerve injury, ipRGCs lacking Tbr2 continue to survive better than non-ipRGCs, albeit to a lesser extent than wildtype ipRGCs. The function of Isl2 in RGC development has not previously been elucidated because Isl2 knockout mice die shortly after birth. Therefore, I designed an Isl2-flox mouse and subsequently generated Isl2 conditional knockout mice in which Isl2 is specifically removed from the retina. I demonstrate that Isl2 is required for the survival of Isl2-expressing RGC subtypes. My work uncovers important roles for Tbr2 and Isl2 in RGC development, maintenance, and survival. Additionally, the generation of a mouse with an Isl2 conditional knockout allele provides a new tool that can be used to study the development of other cell types in which Isl2 is expressed.