Using the mouse retina to model the role of SOX2 in neural induction

Neural competence is the ability of a progenitor cell to generate a neuron. The eye is one of the few tissues derived from the neural ectoderm that contains both neurogenic and non-neurogenic cells, all of which arise from a common progenitor pool. Therefore, the eye is a particularly useful model to study the molecular mechanisms that confer neural competence. Moreover, this cell fate dichotomy is highly reminiscent of the earlier process of neural induction, or the decision of an ectoderm precursor cell to become neural plate or epidermis. The HMG-box transcription factor SOX2 is crucial for both of these processes. Little is known about the role of SOX2 in neural induction, and what is known has been worked out primarily in lower vertebrates. Humans and mice with mutations in SOX2 exhibit a range of neural defects; therefore, from the perspective of human health, it is important to understand SOX2's function in mammalian neuroepithelium. This project takes advantage of the accessibility of the embryonic mouse eye to identify pathways that SOX2 regulates to maintain neural competence. Chapter I gives an overview of neural induction from an historical perspective, with particular attention to the role of SOXB1 factors. A detailed description of mammalian eye development and the similarities between optic cup regionalization and neural induction are described. Chapter II investigates one potential mechanism of how SOX2 specifies neural fate: antagonism of Pax6. Using mouse genetics, we show that ablation of Sox2 in the OC leads to increased Pax6 expression and loss of neural competence. This phenotype is partially rescued by lowering Pax6 in Sox2cond/cond; αP0CreiresGFP cells. Chapter III investigates the increased WNT signaling activity observed upon SOX2 ablation. Using mouse genetics, we show that removal of β-Catenin from Sox2-negative cells rescues some aspects of the Sox2-mutant phenotype. Chapter IV offers some ideas of how these studies potentially relate to the treatment of degenerative eye disease, focusing on identifying candidate genes that could rescue neurogenesis in a Sox2-depleted background. To put these ideas into context, an overview of the current state of gene therapy for the treatment of eye disease is offered.Doctor of Philosoph