SoxC Factors and Their Contribution to the Ocular Complications of CHARGE Syndrome

The formation of the visual system during development involves complex morphogenetic interactions between cells of multiple embryonic lineages. Disruptions in this process are associated with structural birth defects such as microphthalmia, anophthalmia, and coloboma (MAC), and are a common feature of CHARGE syndrome. Although the genetic cause has been identified for most cases of CHARGE syndrome (mutations in CHD7), the mechanistic details of how genetic mutations cause ocular malformations in CHARGE syndrome remain a mystery. We have been studying the function of the SoxC transcription factors Sox4 and Sox11 in ocular development using the zebrafish, a small freshwater fish that is favored for developmental genetic research. Previously, we demonstrated that SoxC factors are required to control levels of Bone morphogenetic protein (Bmp) and Hedgehog (Hh) signaling during ocular morphogenesis. Furthermore, we and others demonstrated that mutations in SOX11 contribute to MAC phenotypes and to CHARGE syndrome in humans. In this proposal, we follow up on our previous work in three specific aims. In Specific Aim 1, we will use state-of-the art lightsheet microscopy to assess the effects of SoxC disruption on the specification of cranial neural crest cells and their periocular derivatives. In Specific Aim 2, we will identify the targets of SoxC factors in neural crest cells. Finally, in Specific Aim 3, we will investigate the connection between Chd7, SoxC factors, and the ocular manifestations of CHARGE syndrome. The results of our work will shed new light on the etiology of the ocular malformations associated with CHARGE syndrome.