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Jeffrey Trimarchi, Greg Martin; Onecut Transcription Factors Play Distinct Roles In The Developing And Mature Retina. Invest. Ophthalmol. Vis. Sci. 2012;53(14):423.
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During the course of retinal development, cycling progenitor cells give rise to a variety of cell types (six neurons and one glia). Previously, in an effort to uncover the intrinsic programs that drive cell fate decisions in these cells, we profiled the gene expression programs of individual progenitor cells that expressed the transcription Math5. We found significant clusters of genes that correlated specifically with distinct subsets of these Math5+ cells. These clusters contained many different transcription factors whose function in the developing retina was unexplored. Here we report on an analysis of retinal development in mice individually deficient for two of these transcription factors, Onecut1 and Onecut2.
We examined the retinas of mice deficient for either Onecut1 or Onecut2 by three main methods. We compared wildtype and knockout retinas by microarray analysis, in situ hybridization and immunohistochemistry. We used a variety of probes and antibodies to examine each of the different retinal cell types in these knockout mice. These analyses were performed at multiple developmental time points and in the adult.
The combination of in situ hybridizations and immunostainings of the Onecut2 deficient adult retinas showed that all of the retinal cell types are present. Interestingly, however, the horizontal cells are significantly reduced. We observed an approximately 50% loss of these cells in the Onecut2 knockout adult retina. Microarray analysis of these retinas showed a consistent decrease in Lhx1, providing a potential explanation for the horizontal cell loss. Onecut1 deficient mice die at birth so their retinas were only analyzed during embryonic development. These mice showed decreases in some of the early born retinal cell types by marker analysis of both microarrays and in situ hybridizations. We are currently trying to decipher which ganglion cell subsets are affected by the loss of Onecut1.
The Onecut transcription factors were found by us and others to be expressed in retinal progenitor cells, at times consistent with when these cells are making cell fate decisions. Analysis of mice deficient for Onecut2 revealed a critical role for this transcription factor in the generation of a percentage of horizontal cells. Loss of Onecut1, on the other hand, revealed additional defects in the generation of other early born retinal cell types.
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