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Miruna G. Ghinia-Tegla, Diego F. Buenaventura, Peter Quinn, Chisom T Madu, Dillon O Rogando, Stephen Tsang, Mark M. Emerson; SALL1 acts downstream of ONECUT1 to repress the rod photoreceptor generation. Invest. Ophthalmol. Vis. Sci. 2021;62(8):2938.
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The proper development of cone and rod photoreceptors (PRs) requires the timed activation of different genetic programs. Alterations in these specific programs trigger developmental defects of cell fate specification, that are likely to yield visual impairments.
Previous reports show that ONECUT1 (OC1) is involved in the repression of gene regulatory networks that trigger rod genesis (Emerson et al., 2013). To explore its contribution in the early decision of photoreceptor (PR) specification, we electroporated CrxEnh1::GFP (active in both cone and rods) and CAG::OC1Enr (a repressor form of OC1), at E5 in the chick retina (Jean-Charles et al., 2018). Transcriptomes of these cells were generated after culturing whole retinas for 2 day in vitro. Several rod-related genes were upregulated, while most cone-related genes were downregulated. We next screened candidate genes to test their involvement in the repression of rod programs, taking the following approach: retinas were electroporated at E5 with a reporter plasmid that drives GFP expression after the activation of the Rhodopsin promoter (Rho::GFP) (Jean-Charles et al., 2018), with either CAG::Enr or CAG::OC1Enr, in addition to an overexpression plasmid, that allowed the forced expression of each candidate genes.
We identified that overexpression of SALL1 was able to reduce the early induction of Rhodopsin triggered by OC1 repression. We confirmed the expression of SALL1 in the cones of the chick retina as well as in the developing human retina, using retinal organoids. In addition, overexpression of SALL1 showed an increase number of RXRG-positive PRs.We also analyzed SALL1 loss-of-function in the developing chick retina using CRISPR/Cas9. We determined that upon SALL1 gene editing, the Rhodopsin promoter was activated and the rod pathway was turned on.
We report for the first time that a cone-enriched gene, SALL1, that acts downstream of OC1 to repress the rod genesis pathway.
This is a 2021 ARVO Annual Meeting abstract.
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