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Single cell profiling of CRISPR/Cas9-induced OTX2 deficient retinas reveals fate switch from restricted progenitors

View ORCID ProfileMiruna G. Ghinia Tegla, Diego F. Buenaventura, Diana Y. Kim, Cassandra Thakurdin, Kevin C. Gonzalez, View ORCID ProfileMark M. Emerson
doi: https://doi.org/10.1101/538710
Miruna G. Ghinia Tegla
1Department of Biology, The City College of New York, City University of New York, New York, NY, 10031; United States of America
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  • ORCID record for Miruna G. Ghinia Tegla
Diego F. Buenaventura
1Department of Biology, The City College of New York, City University of New York, New York, NY, 10031; United States of America
2Biology Ph.D. Program, Graduate Center, City University of New York, New York, NY, 10031; United States of America
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Diana Y. Kim
1Department of Biology, The City College of New York, City University of New York, New York, NY, 10031; United States of America
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Cassandra Thakurdin
1Department of Biology, The City College of New York, City University of New York, New York, NY, 10031; United States of America
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Kevin C. Gonzalez
1Department of Biology, The City College of New York, City University of New York, New York, NY, 10031; United States of America
3Present address: Doctoral Program in Neurobiology and Behavior, Columbia University, New York, NY 10032; United States of America
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Mark M. Emerson
1Department of Biology, The City College of New York, City University of New York, New York, NY, 10031; United States of America
2Biology Ph.D. Program, Graduate Center, City University of New York, New York, NY, 10031; United States of America
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  • ORCID record for Mark M. Emerson
  • For correspondence: memerson@ccny.cuny.edu
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Abstract

Development of the vertebrate eye, like many developmental systems, depends on genes that are used iteratively in multiple distinct processes. The OTX2 transcription factor is one such gene, with a requirement for eye formation, photoreceptor formation, and retinal pigment epithelium specification, among others. Recent evidence has suggested that OTX2 is also expressed in subsets of retinal progenitor cells with restricted fate choices. However, given the multiple roles for OTX2 and limitations of conventional conditional knockout strategies, the functional significance of this expression is unknown. Here we use CRISPR/Cas9 gene editing to produce mutations of OTX2, identifying similar phenotypes to those observed in human patients. In addition, we use single cell RNA sequencing to determine the functional consequences of OTX2 gene editing by CRISPR/Cas9 on the population of cells derived from OTX2-expressing retinal progenitor cells. We not only confirm that OTX2 is required for the generation of photoreceptors, but also for maintaining the proliferative potential of cells and suppressing the formation of specific retinal fates. These include subtypes of retinal ganglion and horizontal cells normally associated with these progenitor types, suggesting that in this context OTX2 functions to repress sister cell fate choices. Upregulation of key transcription factors involved in the formation of these cells was observed suggesting that OTX2 is upstream of critical nodes of gene regulatory networks of these alternative fates.

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Posted February 02, 2019.
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Single cell profiling of CRISPR/Cas9-induced OTX2 deficient retinas reveals fate switch from restricted progenitors
Miruna G. Ghinia Tegla, Diego F. Buenaventura, Diana Y. Kim, Cassandra Thakurdin, Kevin C. Gonzalez, Mark M. Emerson
bioRxiv 538710; doi: https://doi.org/10.1101/538710
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Single cell profiling of CRISPR/Cas9-induced OTX2 deficient retinas reveals fate switch from restricted progenitors
Miruna G. Ghinia Tegla, Diego F. Buenaventura, Diana Y. Kim, Cassandra Thakurdin, Kevin C. Gonzalez, Mark M. Emerson
bioRxiv 538710; doi: https://doi.org/10.1101/538710

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