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标题：Two transcription factors, Pou4f2 and Isl1, are sufficient to specify the retinal ganglion cell fate
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作者：Fuguo Wu ; Tadeusz J. Kaczynski ; Santhosh Sethuramanujam 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：13
页码：E1559-E1568
DOI：10.1073/pnas.1421535112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceDespite the progress made during the last two decades regarding the generation of retinal cell types, the mechanisms by which a retinal progenitor cell decides to adopt a particular cell type remain unclear. Using a binary knockin-transgenic system, we show that two factors, POU domain, class 4, transcription factor 2 (Pou4f2) and insulin gene enhancer protein 1 (Isl1), specify the retinal ganglion cell (RGC) fate and activate the whole gene-expression program required for ganglion cell differentiation. This study, for the first time to our knowledge, defines a set of determinant factors for any retinal cell type, offering significant insight into how cellular diversity is achieved in the central nervous system. It also provides guidance for generating RGCs in vitro for therapeutic purposes. As with other retinal cell types, retinal ganglion cells (RGCs) arise from multipotent retinal progenitor cells (RPCs), and their formation is regulated by a hierarchical gene-regulatory network (GRN). Within this GRN, three transcription factors--atonal homolog 7 (Atoh7), POU domain, class 4, transcription factor 2 (Pou4f2), and insulin gene enhancer protein 1 (Isl1)--occupy key node positions at two different stages of RGC development. Atoh7 is upstream and is required for RPCs to gain competence for an RGC fate, whereas Pou4f2 and Isl1 are downstream and regulate RGC differentiation. However, the genetic and molecular basis for the specification of the RGC fate, a key step in RGC development, remains unclear. Here we report that ectopic expression of Pou4f2 and Isl1 in the Atoh7-null retina using a binary knockin-transgenic system is sufficient for the specification of the RGC fate. The RGCs thus formed are largely normal in gene expression, survive to postnatal stages, and are physiologically functional. Our results indicate that Pou4f2 and Isl1 compose a minimally sufficient regulatory core for the RGC fate. We further conclude that during development a core group of limited transcription factors, including Pou4f2 and Isl1, function downstream of Atoh7 to determine the RGC fate and initiate RGC differentiation.
关键词：retinal development ; neural development ; transcription factors ; cell fate specification ; gene regulation