ISL1 and BRN3B co-regulate the differentiation of murine retinal ganglion cells.
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.
Pan
Ling
L
Department of Ophthalmology, University of Rochester, Rochester, NY 14642, USA.
Deng
Min
M
Xie
Xiaoling
X
Gan
Lin
L
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D060850:LIM-Homeodomain Proteins; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D012160:Retina / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000378:metabolism*; D050820:Transcription Factor Brn-3B / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors
D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; D050820:Transcription Factor Brn-3B; D014157:Transcription Factors; C063843:insulin gene enhancer binding protein Isl-1