The Role of SOX2 in the Development of the Optic Cup, Hypothalamus and Secondary Palate

SOX2 is a HMG domain-containing transcription factor expressed in all neural progenitor cells of the developing and adult nervous system. Several critical properties of neural progenitors, including the ability to self-renew and pluripotency, depend on Sox2 function. SOX2 haploinsufficient humans exhibit abnormalities in tissues that derive from the neural ectoderm and in several facial structures. Previous models of this disorder have been limited in their descriptive ability. The generation of mice hypomorphic for Sox2 (Sox2HYP) has allowed an analysis of Sox2 function in an environment in which its dosage is constitutively lower. A previous study of these mice confirmed their value as a model for SOX2 haploinsufficiency but was limited to later developmental stages; it is therefore unknown (i) what developmental events lead to the observed phenotypes and (ii) whether these mice exhibit other abnormalities observed in cases of SOX2 haploinsufficiency (Taranova, et al., 2006). Therefore, this thesis was undertaken with the following hypotheses: (i) mouse embryos that are hypomorphic for Sox2 (Sox2HYP) will exhibit early ocular, neural, and craniofacial defects that are consistent with the phenotypes that are observed in humans with SOX2 haploinsufficiency, and (ii) the molecular analyses of these developing tissues and structures in the Sox2HYP mouse embryo will provide information regarding the specific function of Sox2 in the development of the brain and eye. It was found that prior to E10.5, Sox2HYP optic primordia do not exhibit altered proliferation or apoptosis; however, abnormal neural retina pattering is observed at E10.5. Furthermore, the optic stalk is hypoplastic, exhibits increased apoptosis, and contributes to an abnormal OC orientation. Also observed was an abnormal broadening of the posterior prechordal floor, a defect encompassing the tuberal hypothalamus and characterized by abnormal expression of genes within the sonic hedgehog (Shh) signaling pathway. This work also illustrates Sox2's participation in secondary palatal development, specifically in the development of the palatal shelves. The palatal abnormality presents at E14.5, affects approximately two-thirds of Sox2HYP pups, and likely does not result from retrognathia. Overall, the tested hypotheses have been proven, providing important information regarding SOX2 haploinsufficiency-related defects that involve the eyes, brain, and secondary palate.Doctor of Philosoph