JAMA · 2021
Half-Dose vs Stable-Dose Conventional Synthetic Disease-Modifying Antirheumatic Drugs and Disease Flare in Patients With Rheumatoid Arthritis.
Письмо в редакциюКомментарийНазвание и аннотация: Перевод в очереди
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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
Аннотация
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.
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.