Zfp503/Nlz2 is Required for RPE Differentiation and Optic Fissure Closure

2022 · doi:10.1101/2022.03.28.486078
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Zfp503 knockout mice exhibit uveal coloboma due to impaired RPE differentiation and altered expression of key developmental transcription factors, impacting optic fissure closure.

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This study investigates how loss of the transcription factor Zfp503 (Znf503/Nlz2) affects uveal coloboma development in mice, focusing on optic fissure closure and retinal pigment epithelium (RPE) differentiation. Using Zfp503 knockout mice generated by homologous recombination, the authors assessed embryonic eye development through histology, immunostaining/in situ hybridization, and RNA sequencing of E11.5 mutant versus wild-type RPE/choroid, finding that Zfp503 expression is dynamic during eye development and that knockout embryos develop uveal coloboma. The key findings were altered expression patterns of multiple eye-development transcription factors (including Otx2, Mitf, Pax6, Pax2, Vax1, and Vax2), failure to maintain presumptive RPE fate with reduced melanin pigmentation and RPE differentiation into a neural retina-like lineage, and RNA-seq overlap with genes known to be regulated at the optic fissure. The paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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Abstract

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 knock down of znf503 (the ortholog of mouse Zfp503) in zebrafish causes coloboma. Here we characterize Zfp503 knock out (KO) mice and evaluate transcriptomic profiling of mutant vs. 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 that 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 reduced melanin pigmentation in the presumptive RPE and its differentiation into neural-retina-like lineages. Comparison of RNA-Seq data from wild type 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 RPE differentiation and in optic fissure closure.
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Zfp503/Nlz2 Is Required for RPE Differentiation and Optic Fissure Closure. Published version Peer-reviewed Repository URI Repository DOI Change log Abstract 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. Description Funder: Wellcome Trust Funder: Cancer Research UK Funder: Medical Research Council Journal Title Conference Name Journal ISSN 1552-5783

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