期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 292, 期 52, 页码 21442-21456出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA117.000141
关键词
Joubert syndrome; photoreceptor; cilia; retinal degeneration; guanine nucleotide exchange factor (GEF); small GTPase; ARL13b; ARL3-GTP; ciliogenesis; transition zone; photoreceptor outer segment
资金
- National Institutes of Health [EY08123, EY019298]
- NEI, National Institutes of Health [EY014800-039003]
- Research to Prevent Blindness (RPB) (New York)
Arf-like protein 13b (ARL13b) is a small GTPase that functions as a guanosine nucleotide exchange factor (GEF) for ARL3-GDP. ARL13b is located exclusively in photoreceptor outer segments (OS) presumably anchored to discs by palmitoylation, whereas ARL3 is an inner segment cytoplasmic protein. Hypomorphic mutations affecting the ARL13b G-domain inactivate GEF activity and lead to Joubert syndrome (JS) in humans. However, the molecular mechanisms in ARL13b mutation-induced Joubert syndrome, particularly the function of primary cilia, are still incompletely understood. Because Arl13b germline knockouts in mouse are lethal, we generated retina-specific deletions of ARL13b in which ARL3-GTP formation is impaired. In mouse (ret)Arl13b(-/-) central retina at postnatal day 6 (P6) and older, outer segments were absent, thereby preventing trafficking of outer segment proteins to their destination. Ultrastructure of postnatal day 10 (P10) central (ret)Arl13b(-/-) photoreceptors revealed docking of basal bodies to cell membranes, but mature transition zones and disc structures were absent. Deletion of ARL13b in adult mice via tamoxifen-induced Cre/loxP recombination indicated that axonemes gradually shorten and outer segments progressively degenerate. IFT88, essential for anterograde intraflagellar transport (IFT), was significantly reduced at (tam)Arl13b(-/-) basal bodies, suggesting impairment of intraflagellar transport. AAV2/8 vector-mediated ARL13b expression in the (ret)Arl13b(-/-) retina rescued ciliogenesis.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据