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

Author:

Kobayashi Yuka1,Watanabe Shizuka2,Ong Agnes Lee Chen2,Shirai Manabu3ORCID,Yamashiro Chiemi1,Ogata Tadahiko1,Higashijima Fumiaki1,Yoshimoto Takuya1ORCID,Hayano Takahide4,Asai Yoshiyuki4,Sasai Noriaki2ORCID,Kimura Kazuhiro1ORCID

Affiliation:

1. Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-kogushi, Ube 755-0046, Japan

2. Developmental Biomedical Science, Division of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama-cho, Ikoma 630-0192, Japan

3. Omics Research Center (ORC), National Cerebral and Cardiovascular Center, 6-1 Kishibe Shinmachi, Suita, Osaka 564-8565, Japan

4. Department of Systems Bioinformatics, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-kogushi, Ube 755-0046, Japan

Abstract

ABSTRACT 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.

Funder

Japan Society for the Promotion of Science

Novartis Pharma

Publisher

The Company of Biologists

Subject

General Biochemistry, Genetics and Molecular Biology,Immunology and Microbiology (miscellaneous),Medicine (miscellaneous),Neuroscience (miscellaneous)

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