Journal
DEVELOPMENT
Volume 135, Issue 11, Pages 1981-1990Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dev.010751
Keywords
LIM-homeodomain; POU domain; MATH5; ATOH7; POU4F2; RGC; retinal development; transcription factor
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Funding
- NEI NIH HHS [R01 EY013426-06A1, R01 EY015551-04, EY015551, R01 EY013426, R01 EY015551, EY013426, R01 EY013426-07] Funding Source: Medline
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LIM-homeodomain (HD) and POU-HD transcription factors play crucial roles in neurogenesis. However, it remains largely unknown how they cooperate in this process and what downstream target genes they regulate. Here, we show that ISL1, a LIM-HD protein, is co-expressed with BRN3B, a POU-HD factor, in nascent post-mitotic retinal ganglion cells (RGCs). Similar to the Brn3b-null retinas, retina-specific deletion of Isl1 results in the apoptosis of a majority of RGCs and in RGC axon guidance defects. The Isl1 and Brn3b double null mice display more severe retinal abnormalities with a near complete loss of RGCs, indicating the synergistic functions of these two factors. Furthermore, we show that both Isl1 and Brn3b function downstream of Math5 to regulate the expression of a common set of RGC-specific genes. Whole-retina chromatin immunoprecipitation and in vitro transactivation assays reveal that ISL1 and BRN3B concurrently bind to and synergistically regulate the expression of a common set of RGC-specific genes. Thus, our results uncover a novel regulatory mechanism of BRN3B and ISL1 in RGC differentiation.
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