PUBLICATION
Zfp503/Nlz2 Is Required for RPE Differentiation and Optic Fissure Closure
- Authors
- Boobalan, E., Thompson, A.H., Alur, R.P., McGaughey, D.M., Dong, L., Shih, G., Vieta-Ferrer, E.R., Onojafe, I.F., Kalaskar, V.K., Arno, G., Lotery, A.J., Guan, B., Bender, C., Memon, O., Brinster, L., Soleilhavoup, C., Panman, L., Badea, T.C., Minella, A., Lopez, A.J., Thomasy, S.M., Moshiri, A., Blain, D., Hufnagel, R.B., Cogliati, T., Bharti, K., Brooks, B.P.
- ID
- ZDB-PUB-221104-10
- Date
- 2022
- Source
- Investigative ophthalmology & visual science 63: 5 (Journal)
- Registered Authors
- Brooks, Brian P.
- Keywords
- none
- MeSH Terms
-
- Animals
- Coloboma*/genetics
- Coloboma*/metabolism
- Gene Expression Regulation, Developmental
- Homeodomain Proteins/genetics
- Humans
- Intracellular Signaling Peptides and Proteins/metabolism
- Melanins/metabolism
- Mice
- Mice, Knockout
- Nerve Tissue Proteins/genetics
- Neuropeptides*/genetics
- Retina/metabolism
- Retinal Pigment Epithelium/metabolism
- Zebrafish/genetics
- PubMed
- 36326727 Full text @ Invest. Ophthalmol. Vis. Sci.
Citation
Boobalan, E., Thompson, A.H., Alur, R.P., McGaughey, D.M., Dong, L., Shih, G., Vieta-Ferrer, E.R., Onojafe, I.F., Kalaskar, V.K., Arno, G., Lotery, A.J., Guan, B., Bender, C., Memon, O., Brinster, L., Soleilhavoup, C., Panman, L., Badea, T.C., Minella, A., Lopez, A.J., Thomasy, S.M., Moshiri, A., Blain, D., Hufnagel, R.B., Cogliati, T., Bharti, K., Brooks, B.P. (2022) Zfp503/Nlz2 Is Required for RPE Differentiation and Optic Fissure Closure. Investigative ophthalmology & visual science. 63:5.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping