Early manifestations and differential gene expression associated with photoreceptor degeneration in Prom1-deficient retina.

Disease models & mechanisms 2021 Nov 01

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Retinitis pigmentosa (RP) and macular dystrophy (MD) are characterized by gradual photoreceptor death in the retina and are often associated with genetic mutations, including those in the prominin-1 (Prom1) gene. Prom1-knockout (KO) mice recapitulate key features of these diseases including light-dependent retinal degeneration and constriction of retinal blood vessels. The mechanisms underlying such degeneration have remained unclear, however. We here analysed early events associated with retinal degeneration in Prom1-KO mice. We found that photoreceptor cell death and glial cell activation occur between 2 and 3 weeks after birth. Whereas gene expression was not affected at 2 weeks, the expression of several genes was altered at 3 weeks in the Prom1-KO retina, with the expression of that for endothelin-2 (Edn2) being markedly upregulated. Expression of Edn2 was also induced by light stimulation in Prom1-KO mice reared in the dark. Treatment with endothelin receptor antagonists attenuated photoreceptor cell death, gliosis and retinal vessel stenosis in Prom1-KO mice. Our findings thus reveal early manifestations of retinal degeneration in a model of RP/MD and suggest potential therapeutic agents for these diseases. This article has an associated First Person interview with the first author of the paper. © 2021. Published by The Company of Biologists Ltd.

Citation

Yuka Kobayashi, Shizuka Watanabe, Agnes Lee Chen Ong, Manabu Shirai, Chiemi Yamashiro, Tadahiko Ogata, Fumiaki Higashijima, Takuya Yoshimoto, Takahide Hayano, Yoshiyuki Asai, Noriaki Sasai, Kazuhiro Kimura. Early manifestations and differential gene expression associated with photoreceptor degeneration in Prom1-deficient retina. Disease models & mechanisms. 2021 Nov 01;14(11)