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Zfp503/Nlz2 Is Required for RPE Differentiation and Optic Fissure Closure
PURPOSE: Uveal coloboma is a congenital eye malformation caused by failure of the optic fissure to close in early human development. Despite significant progress in identifying genes whose regulation is important for executing this closure, mutations are detected in a minority of cases using known g...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Association for Research in Vision and Ophthalmology
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9645360/ https://www.ncbi.nlm.nih.gov/pubmed/36326727 http://dx.doi.org/10.1167/iovs.63.12.5 |
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author | Boobalan, Elangovan Thompson, Amy H. Alur, Ramakrishna P. McGaughey, David M. Dong, Lijin Shih, Grace Vieta-Ferrer, Emile R. Onojafe, Ighovie F. Kalaskar, Vijay K. Arno, Gavin Lotery, Andrew J. Guan, Bin Bender, Chelsea Memon, Omar Brinster, Lauren Soleilhavoup, Clement Panman, Lia Badea, Tudor C. Minella, Andrea Lopez, Antonio Jacobo Thomasy, Sara M. Moshiri, Ala Blain, Delphine Hufnagel, Robert B. Cogliati, Tiziana Bharti, Kapil Brooks, Brian P. |
author_facet | Boobalan, Elangovan Thompson, Amy H. Alur, Ramakrishna P. McGaughey, David M. Dong, Lijin Shih, Grace Vieta-Ferrer, Emile R. Onojafe, Ighovie F. Kalaskar, Vijay K. Arno, Gavin Lotery, Andrew J. Guan, Bin Bender, Chelsea Memon, Omar Brinster, Lauren Soleilhavoup, Clement Panman, Lia Badea, Tudor C. Minella, Andrea Lopez, Antonio Jacobo Thomasy, Sara M. Moshiri, Ala Blain, Delphine Hufnagel, Robert B. Cogliati, Tiziana Bharti, Kapil Brooks, Brian P. |
author_sort | Boobalan, Elangovan |
collection | PubMed |
description | PURPOSE: Uveal coloboma is a congenital eye malformation caused by failure of the optic fissure to close in early human development. Despite significant progress in identifying genes whose regulation is important for executing this closure, mutations are detected in a minority of cases using known gene panels, implying additional genetic complexity. We have previously shown knockdown of znf503 (the ortholog of mouse Zfp503) in zebrafish causes coloboma. Here we characterize Zfp503 knockout (KO) mice and evaluate transcriptomic profiling of mutant versus wild-type (WT) retinal pigment epithelium (RPE)/choroid. METHODS: Zfp503 KO mice were generated by gene targeting using homologous recombination. Embryos were characterized grossly and histologically. Patterns and level of developmentally relevant proteins/genes were examined with immunostaining/in situ hybridization. The transcriptomic profile of E11.5 KO RPE/choroid was compared to that of WT. RESULTS: Zfp503 is dynamically expressed in developing mouse eyes, and loss of its expression results in uveal coloboma. KO embryos exhibit altered mRNA levels and expression patterns of several key transcription factors involved in eye development, including Otx2, Mitf, Pax6, Pax2, Vax1, and Vax2, resulting in a failure to maintain the presumptive RPE, as evidenced by reduced melanin pigmentation and its differentiation into a neural retina–like lineage. Comparison of RNA sequencing data from WT and KO E11.5 embryos demonstrated reduced expression of melanin-related genes and significant overlap with genes known to be dynamically regulated at the optic fissure. CONCLUSIONS: These results demonstrate a critical role of Zfp503 in maintaining RPE fate and optic fissure closure. |
format | Online Article Text |
id | pubmed-9645360 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | The Association for Research in Vision and Ophthalmology |
record_format | MEDLINE/PubMed |
spelling | pubmed-96453602022-11-15 Zfp503/Nlz2 Is Required for RPE Differentiation and Optic Fissure Closure Boobalan, Elangovan Thompson, Amy H. Alur, Ramakrishna P. McGaughey, David M. Dong, Lijin Shih, Grace Vieta-Ferrer, Emile R. Onojafe, Ighovie F. Kalaskar, Vijay K. Arno, Gavin Lotery, Andrew J. Guan, Bin Bender, Chelsea Memon, Omar Brinster, Lauren Soleilhavoup, Clement Panman, Lia Badea, Tudor C. Minella, Andrea Lopez, Antonio Jacobo Thomasy, Sara M. Moshiri, Ala Blain, Delphine Hufnagel, Robert B. Cogliati, Tiziana Bharti, Kapil Brooks, Brian P. Invest Ophthalmol Vis Sci Genetics PURPOSE: Uveal coloboma is a congenital eye malformation caused by failure of the optic fissure to close in early human development. Despite significant progress in identifying genes whose regulation is important for executing this closure, mutations are detected in a minority of cases using known gene panels, implying additional genetic complexity. We have previously shown knockdown of znf503 (the ortholog of mouse Zfp503) in zebrafish causes coloboma. Here we characterize Zfp503 knockout (KO) mice and evaluate transcriptomic profiling of mutant versus wild-type (WT) retinal pigment epithelium (RPE)/choroid. METHODS: Zfp503 KO mice were generated by gene targeting using homologous recombination. Embryos were characterized grossly and histologically. Patterns and level of developmentally relevant proteins/genes were examined with immunostaining/in situ hybridization. The transcriptomic profile of E11.5 KO RPE/choroid was compared to that of WT. RESULTS: Zfp503 is dynamically expressed in developing mouse eyes, and loss of its expression results in uveal coloboma. KO embryos exhibit altered mRNA levels and expression patterns of several key transcription factors involved in eye development, including Otx2, Mitf, Pax6, Pax2, Vax1, and Vax2, resulting in a failure to maintain the presumptive RPE, as evidenced by reduced melanin pigmentation and its differentiation into a neural retina–like lineage. Comparison of RNA sequencing data from WT and KO E11.5 embryos demonstrated reduced expression of melanin-related genes and significant overlap with genes known to be dynamically regulated at the optic fissure. CONCLUSIONS: These results demonstrate a critical role of Zfp503 in maintaining RPE fate and optic fissure closure. The Association for Research in Vision and Ophthalmology 2022-11-03 /pmc/articles/PMC9645360/ /pubmed/36326727 http://dx.doi.org/10.1167/iovs.63.12.5 Text en Copyright 2022 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. |
spellingShingle | Genetics Boobalan, Elangovan Thompson, Amy H. Alur, Ramakrishna P. McGaughey, David M. Dong, Lijin Shih, Grace Vieta-Ferrer, Emile R. Onojafe, Ighovie F. Kalaskar, Vijay K. Arno, Gavin Lotery, Andrew J. Guan, Bin Bender, Chelsea Memon, Omar Brinster, Lauren Soleilhavoup, Clement Panman, Lia Badea, Tudor C. Minella, Andrea Lopez, Antonio Jacobo Thomasy, Sara M. Moshiri, Ala Blain, Delphine Hufnagel, Robert B. Cogliati, Tiziana Bharti, Kapil Brooks, Brian P. Zfp503/Nlz2 Is Required for RPE Differentiation and Optic Fissure Closure |
title | Zfp503/Nlz2 Is Required for RPE Differentiation and Optic Fissure Closure |
title_full | Zfp503/Nlz2 Is Required for RPE Differentiation and Optic Fissure Closure |
title_fullStr | Zfp503/Nlz2 Is Required for RPE Differentiation and Optic Fissure Closure |
title_full_unstemmed | Zfp503/Nlz2 Is Required for RPE Differentiation and Optic Fissure Closure |
title_short | Zfp503/Nlz2 Is Required for RPE Differentiation and Optic Fissure Closure |
title_sort | zfp503/nlz2 is required for rpe differentiation and optic fissure closure |
topic | Genetics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9645360/ https://www.ncbi.nlm.nih.gov/pubmed/36326727 http://dx.doi.org/10.1167/iovs.63.12.5 |
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