NRL, a bZIP protein, is a key transcription factor involved in controlling expression of most genes expressed in rod photoreceptors. NRL interacts with TATA-binding protein (TBP), CRX, NR2E3, SP4 and many other transcriptional regulatory factors to control gene expression. Loss of NRL in mouse leads to functional transformation of rods to cone photoreceptors, whereas expression of NRL in committed cone precursors can convert these cells to rod photoreceptors. Using NRL-promoter, we have been able to express green fluorescent protein in mouse rod photoreceptors as soon as they are born and flow-sort these cells at different stages of development and aging for gene profiling, transplantation and other research purposes. We are using photoreceptor gene profiles to construct NRL-regulatory network underlying functional maturation of rods. In addition, in silico and chromatin immunoprecipitation-based methods and high throughput sequencing are being employed to identify direct targets of NRL and other retinal transcription factors. We are also interested in examining how gene expression changes during the aging of photoreceptors affect visual function. ? ? To understand the regulation of NRL expression during photoreceptor differentiation and in mature retina, we are dissecting cis- elements in the promoter of NRL and identifying regulatory transcription factors. Our results point to bHLH proteins and nuclear receptors. To delineate post-translational modifications that control the activity of NRL, we are examining SUMOylation and phosphorylation of NRL and corresponding signaling pathways. We have shown that Nrl is SUMOylated, and PIAS3 is one of the proteins involved in this process. We have some early suggestive evidence that GSK3-β and MAPKs play important roles in NRL phosphorylation and in controlling its activity. These fundamental studies have provided significant new insights into photoreceptor biology and disease.
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