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R. Yan, S. Wang; Engrailed-mediated Repression of NeuroD Specifically Inhibits Photoreceptor Production in the Chick Retina . Invest. Ophthalmol. Vis. Sci. 2003;44(13):2811.
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Purpose: The genetic control of photoreceptor cell fate in the vertebrate retina is poorly understood. Previously, our gain-of-function studies indicate that NeuroD, a proneural bHLH gene, is sufficient to induce overproduction of photoreceptor in the developing chick retina and de novo generation of photoreceptor cells from RPE cell culture. The current study investigates whether repression of NeuroD will specifically reduce the photoreceptor production. Methods: The entire repressor domain of Drosophila Engrailed, or the its D-domain, was fused in frame with chick NeuroD lacking its transactivation domain, generating active repression constructs En-NeuroDΔC and dEN-NeuroDΔC. Replication-competent retroviruses (RCAS) expressing these repression constructs were microinjected into the chick subretinal space. Retinas were fixed and analyzed with various markers to identify the different types of retinal neurons and their synaptic processes. Results: Embryos infected with retrovirus RCAS expressing active repression constructs exhibited severe photoreceptor deficits: the ONL was no longer a contiguous structure, but became fragmented with breaks that contained less or no photoreceptor cells. Contrary to the profound photoreceptor deficit, no deficits were found in Chx10+ bipolar cells, AP2+ amacrine cells, and Brn3A+ ganglion cells. Development of the IPL appeared normal, even at those places where the retina lacked photoreceptor cells. In normal retina, Chx10+ cells are confined within the inner nuclear layer. However, in retinas infected with RCAS-En-NeuroDΔC, Chx10+ cells were found in the ONL, where young photoreceptor cells reside. The presence of Chx10+ cells in the ONL was observed only around E10. Conclusions: Repression of NeuroD specifically reduces the production of photoreceptor cells in the developing chick retina, suggesting a specific role of NeuroD in the genesis of photoreceptor cells. The transient presence of Chx10+ cells in the ONL implies that repression of NeuroD by Engrailed might switch the original, photoreceptor fate to a bipolar fate.
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