National Eye Institute 5R01EY034455-04

Molecular underpinnings of photoreceptor transcriptional regulation by CRX and NRL

This award funds research to determine the structures of CRX and NRL transcription factors bound to DNA to understand their role in photoreceptor development and retinal diseases, aiding targeted therapy development.

Description

Two key transcription factors, homeodomain protein CRX and basic leucine zipper protein NRL, are at the center of gene regulation during photoreceptor differentiation and homeostasis. CRX is essential for specifying commitment of postmitotic photoreceptor precursors to the development of photoreceptor cells, whereas NRL determines the rod cell fate. In orchestrating the transcriptional program of photoreceptor development, CRX and NRL cooperate functionally and physically via a direct protein-protein interaction. Defects in photoreceptor transcriptional regulation due to mutations in the genes encoding CRX and NRL cause severe retinal diseases including retinitis pigmentosa, cone-rod dystrophy, and Leber congenital amaurosis. Despite our advanced understanding of the biology and transcriptional networks of CRX and NRL, mechanistic insight into the functions and unique synergy of these transcription factors at the atomic level is lacking. The proposed studies aim to determine the crystal and solution structures of the individual DNA-bound complexes of CRX and NRL, as well as the structure of the ternary CRX/NRL/DNA complex. These structures will help elucidate how disease-causing mutations in CRX and NRL alter DNA-binding specificity and gene regulation, ultimately enabling targeted therapeutic design.

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