Understanding the Function of CHD7 during Retinal Development and the Ocular Complications of CHARGE Syndrome

Grants and Contracts Details

Description

The retinal neurons arise from a common pool of progenitor cells that are regulated by a complex set of genes that precisely give rise to all retinal neurons. Any disruption in this developmental mechanism leads to congenital retinal disorders. Of particular interest to us is the ocular malformations observed in patients with CHARGE syndrome. Common features of this disorder are coloboma, heart defects, atresia choanae, growth retardation, genital and ear abnormalities. The syndrome is caused by mutations in the gene CHD7. Although large number of patients present coloboma, visual impairment is also observed in patients without coloboma suggesting that chd7 is also involved in mechanisms during retinal development. Loss of CHD7 leads to reduced number of cone photoreceptors and truncated photoreceptor outer segments. Our lab has shown that CHD7 is broadly expressed in the retinal progenitors at 24 hpf and retains strong expression in the ganglion cell layer, inner nuclear layer, and photoreceptors by the end of progenitor differentiation into retinal neurons. Morpholino experiments in chd7 show a reduced number of ganglion cells in the morphants. However, the molecular mechanisms and function of chd7 during retinal development has not been rigorously investigated. In this proposal, I aim to investigate the early roles of chd7 during retinal ganglion and photoreceptor cell development utilizing maternal zygotic chd7 mutants in zebrafish which show phenotypes observed in CHRAGE syndrome. I propose to perform scRNA-seq analysis at various early time points and utilize a novel CUT&RUN technique established in zebrafish to impinge upon the temporal dynamics of chd7 binding target regulatory elements. Our lab has established and generated preliminary data utilizing both techniques. Taken together, our analysis will show novel insights into how the loss of chd7 impacts retinal progenitor cell differentiation into the retinal neurons both indirectly and directly including the potential temporal change in chd7 binding activity during retinal development. This analysis could help provide insights into the development of potential therapeutics for treatment of visual impairment in patients with CHARGE syndrome.
StatusActive
Effective start/end date7/1/2310/16/24

Funding

  • Knights Templar Eye Foundation Inc: $90,000.00

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