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Darshan Sapkota, Fuguo Wu, Xiuqian Mu; Redundant Roles for Oc1 and Oc2 in Mouse Retinal Development. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5155.
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Onecut1 (Oc1) and onecut2 (Oc2), members of the onecut transcription factor family, share a high sequence similarity in their DNA binding domains and bind to identical cis-elements. Previously we have shown that Oc1 and Oc2 are expressed in developing retinal ganglion cells (RGCs) and horizontal cells (HCs), and some retinal progenitor cells. Oc1 knockout mice show a significant decrease in the genesis of HCs but no apparent defect in the development or maintenance of RGCs. This has led us to hypothesize that Oc1 and Oc2 act redundantly to regulate retinal development.
Double retina-specific knockout of Oc1 and Oc2 was generated by crossing Oc1-flox and Oc2-flox alleles with the Six3-Cre transgenic mouse line, and the double knockout retinas were examined by histological and immunofluorescent staining.
In Oc1- or Oc2- single knockout retinas, there was no overt defect in RGCs. However, the double knockout mice exhibit a markedly thinner optic nerve compared to littermate control, postnatal day (P) 22, indicating reduced number of RGCs. Consistently, decreased numbers of Pou4f2- and Calbindin-positive cells in the ganglion cell layer were observed. In Oc1-knockout retina, there is a ~80% reduction of HCs. All the residual HCs expressed Oc2, suggesting that Oc2 may be responsible for these cells. In agreement with this hypothesis, in Oc1/Oc2 double knockout retina, there was a complete absence of HCs and the outer plexiform layer completely diminished. Currently, we are in the process of uncovering the cellular and molecular mechanisms underlying these anomalies in Oc1/Oc2 double knockout retina.
The Onecut genes are likely involved in the development of both RGCs and HCs. Since less severe defects were observed in single knockouts than the double knockout, they appear to function redundantly in controlling the formation of these two cell types, likely through regulating common downstream target genes.
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