SOX2 Is Essential for the Maturation and Maintenance of Retinal Müller Glia

Muller glia (MG) are the principal glial cell of the vertebrate retina. The last cell to divide from a multipotent retinal progenitor cell, they maintain many stem cell characteristics including the expression of the HMG-box transcription factor Sox2. In this thesis, we explore the role of Sox2, a marker of pluripotency throughout the CNS, in this population of presumptive neural stem cells, the MG. Through glial specific ablation of Sox2 we demonstrate that SOX2 plays an essential role in the maturation and maintenance of MG in the murine retina. Loss of SOX2 at P5 results in aberrant development and extension of MG side processes that ensheathe the neuronal cell bodies and neurites in the retina. Additionally, MG cell bodies are disorganized and their end feet fail to properly form the limiting membranes of the retina. As a result, neuronal processes in the synaptic plexiform layers are disorganized, accompanied by a marked reduction in inner retinal function. These data indicate a role for Sox2 in guiding the structural development of MG, as well as providing new insights into the role of MG in the maturation of the neural retina. Additionally we address the complex regulation of SOX2 in the retina by examining SOX2 expression in the mildly hypomorphic Sox2Cond line in two different strain backgrounds: on the inbred C57BL6/J background and on a mixed, outbred CD1 background. On a CD1 background, mice heterozygous for the Sox2Cond allele display only a mild reduction in SOX2 expression and display no phenotypic abnormalities. However, SOX2 expression is significantly reduced on the C57BL6/J background compared to wild type levels, accompanied by a marked reduction in retinal function that degenerates over the animal's lifetime. Further, Muller glial specific ablation in the C57BL6/J background results in almost complete loss of retinal function and a slow loss of MG cells over time. Together these results demonstrate the essential role of SOX2 in the maturation of MG and the neural retina, as well as pointing to a role for SOX2 in the maintenance of retinal and MG structure and function in the compromised retina.Doctor of Philosoph