Deletion of the phosphatase INPP5E in the murine retina impairs photoreceptor axoneme formation and prevents disc morphogenesis.
| Autor: | Sharif AS; Department of Ophthalmology, University of Utah Health Science Center, Salt Lake City, Utah, USA., Gerstner CD; Department of Ophthalmology, University of Utah Health Science Center, Salt Lake City, Utah, USA., Cady MA; Department of Ophthalmology, Duke University, Durham, North Carolina, USA., Arshavsky VY; Department of Ophthalmology, Duke University, Durham, North Carolina, USA., Mitchell C; Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia., Ying G; Department of Ophthalmology, University of Utah Health Science Center, Salt Lake City, Utah, USA., Frederick JM; Department of Ophthalmology, University of Utah Health Science Center, Salt Lake City, Utah, USA., Baehr W; Department of Ophthalmology, University of Utah Health Science Center, Salt Lake City, Utah, USA; Department of Neurobiology & Anatomy, University of Utah, Salt Lake City, Utah, USA; Department of Biology, University of Utah, Salt Lake City, Utah, USA. Electronic address: wbaehr@hsc.utah.edu. |
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| Jazyk: | angličtina |
| Zdroj: | The Journal of biological chemistry [J Biol Chem] 2021 Jan-Jun; Vol. 296, pp. 100529. Date of Electronic Publication: 2021 Mar 10. |
| DOI: | 10.1016/j.jbc.2021.100529 |
| Abstrakt: | INPP5E, also known as pharbin, is a ubiquitously expressed phosphatidylinositol polyphosphate 5-phosphatase that is typically located in the primary cilia and modulates the phosphoinositide composition of membranes. Mutations to or loss of INPP5E is associated with ciliary dysfunction. INPP5E missense mutations of the phosphatase catalytic domain cause Joubert syndrome in humans-a syndromic ciliopathy affecting multiple tissues including the brain, liver, kidney, and retina. In contrast to other primary cilia, photoreceptor INPP5E is prominently expressed in the inner segment and connecting cilium and absent in the outer segment, which is a modified primary cilium dedicated to phototransduction. To investigate how loss of INPP5e causes retina degeneration, we generated mice with a retina-specific KO (Inpp5e F/F ;Six3Cre, abbreviated as ret Inpp5e -/- ). These mice exhibit a rapidly progressing rod-cone degeneration resembling Leber congenital amaurosis that is nearly completed by postnatal day 21 (P21) in the central retina. Mutant cone outer segments contain vesicles instead of discs as early as P8. Although P10 mutant outer segments contain structural and phototransduction proteins, axonemal structure and disc membranes fail to form. Connecting cilia of ret Inpp5e -/- rods display accumulation of intraflagellar transport particles A and B at their distal ends, suggesting disrupted intraflagellar transport. Although INPP5E ablation may not prevent delivery of outer segment-specific proteins by means of the photoreceptor secretory pathway, its absence prevents the assembly of axonemal and disc components. Herein, we suggest a model for INPP5E-Leber congenital amaurosis, proposing how deletion of INPP5E may interrupt axoneme extension and disc membrane elaboration. Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.) |
| Databáze: | MEDLINE |
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