Disruptions in eye development are associated with structural birth defects such as microphthalmia, anophthalmia, and coloboma (collectively referred to as MAC), and are a significant cause of pediatric blindness. Ocular abnormalities often occur alongside those of brain and craniofacial defects, highlighting the significant signaling interactions between the developing structures of the head; indeed, MAC is a common feature of systemic congenital malformation syndromes. One example is CHARGE syndrome, a genetic neural cristopathy characterized by coloboma, heart defects, choanal atresia, growth retardation, genital abnormalities, and ear abnormalities. Mutations in chromodomain helicase binding protein 7 (CHD7) and defects in neural crest cell development and migration have been implicated in the pathogenesis of CHARGE syndrome, however the mechanisms underlying the ocular birth defects observed in CHARGE patients have not been identified. Our laboratory studies the development of the vertebrate visual system using zebrafish (Danio rerio). Previous work from our lab has shown that knockdown of Sox11, a member of the SoxC family of transcription factors, in zebrafish results in microphthalmia, coloboma, brain, trunk, and heart defects, all phenotypes observed in CHARGE syndrome. Furthermore, we found that Sox11 is required for the expression of Bone morphogenic proteins (BMPs) during ocular development. In humans, a duplication of Sox11 has been identified in a patient clinically diagnosed with CHARGE syndrome, and CHD7 has been shown to directly interact with Sox11 and Sox4 in neural stem cells. Based on these data, my central hypothesis is that the loss of Sox 11 expression leads to disruptions in neural crest cell dynamics as well as alterations in BMP signaling during development. This hypothesis will be tested in the following aims 1) Determine the role that Sox11 and Chd7 play in the specification, proliferation, survival, and migration of cranial neural crest cells, and 2) Determine whether Sox11 and Chd7 deficiency alters cranial BMP signaling. This proposal will employ innovative and cutting edge live imaging techniques, as well as advanced biochemical and molecular biology approaches, and will leverage the power of the zebrafish model to tackle an important problem in ocular pediatric genetics. Successful completion of this project will define the role of Sox11 in the pathogenesis of the ocular defects such as those observed in CHARGE syndrome and make progress towards improving the identification, management, and treatment of congenital eye malformations. Additionally, this predoctoral proposal allows the candidate to develop unique technical, critical thinking, and effective communication skills crucial to a physician-scientist specializing in ophthalmic pediatric genetics. !
Microphthalmia, anophthalmia, and coloboma (collectively referred to as MAC) are congenital ocular disorders that are a significant cause of visual impairment. The proposed research will define the role of protein coding gene Sox11 in development of the eye, and will determine if defects in Sox11 cause inherited eye diseases. Findings from this project will further our understanding of eye formation during fetal development, and provide avenues for future treatments of inherited eye diseases. !
