Journal article
BBSome function is required for both the morphogenesis and maintenance of the photoreceptor outer segment
PLoS genetics, Vol.13(10), e1007057
10/2017
DOI: 10.1371/journal.pgen.1007057
PMCID: PMC5663628
PMID: 29049287
Abstract
Genetic mutations disrupting the structure and function of primary cilia cause various inherited retinal diseases in humans. Bardet-Biedl syndrome (BBS) is a genetically heterogeneous, pleiotropic ciliopathy characterized by retinal degeneration, obesity, postaxial polydactyly, intellectual disability, and genital and renal abnormalities. To gain insight into the mechanisms of retinal degeneration in BBS, we developed a congenital knockout mouse of Bbs8, as well as conditional mouse models in which function of the BBSome (a protein complex that mediates ciliary trafficking) can be temporally inactivated or restored. We demonstrate that BBS mutant mice have defects in retinal outer segment morphogenesis. We further demonstrate that removal of Bbs8 in adult mice affects photoreceptor function and disrupts the structural integrity of the outer segment. Notably, using a mouse model in which a gene trap inhibiting Bbs8 gene expression can be removed by an inducible FLP recombinase, we show that when BBS8 is restored in immature retinas with malformed outer segments, outer segment extension can resume normally and malformed outer segment discs are displaced distally by normal outer segment structures. Over time, the retinas of the rescued mice become morphologically and functionally normal, indicating that there is a window of plasticity when initial retinal outer segment morphogenesis defects can be ameliorated.
Details
- Title: Subtitle
- BBSome function is required for both the morphogenesis and maintenance of the photoreceptor outer segment
- Creators
- Ying Hsu - Department of Pediatrics, University of Iowa, Iowa City, Iowa, United StatesJanelle E Garrison - Department of Pediatrics, University of Iowa, Iowa City, Iowa, United StatesGunhee Kim - Department of Pediatrics, University of Iowa, Iowa City, Iowa, United StatesAddison R Schmitz - Department of Pediatrics, University of Iowa, Iowa City, Iowa, United StatesCharles C Searby - Department of Pediatrics, University of Iowa, Iowa City, Iowa, United StatesQihong Zhang - Department of Pediatrics, University of Iowa, Iowa City, Iowa, United StatesPoppy Datta - Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, Iowa, United StatesDarryl Y Nishimura - Department of Pediatrics, University of Iowa, Iowa City, Iowa, United StatesSeongjin Seo - Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, Iowa, United StatesVal C Sheffield - Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, Iowa, United States
- Resource Type
- Journal article
- Publication Details
- PLoS genetics, Vol.13(10), e1007057
- DOI
- 10.1371/journal.pgen.1007057
- PMID
- 29049287
- PMCID
- PMC5663628
- NLM abbreviation
- PLoS Genet
- ISSN
- 1553-7390
- eISSN
- 1553-7404
- Publisher
- United States
- Grant note
- DOI: 10.13039/100000002, name: National Institutes of Health, award: EY011298; DOI: 10.13039/100000002, name: National Institutes of Health, award: EY017168; DOI: 10.13039/100000002, name: National Institutes of Health, award: EY022616; DOI: 10.13039/100001024, name: Roy J. Carver Charitable Trust; DOI: 10.13039/100000002, name: National Institutes of Health, award: EY025580; DOI: 10.13039/100000002, name: National Institutes of Health, award: SIG grant 1 S10 RR018998-01
- Language
- English
- Date published
- 10/2017
- Academic Unit
- Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Medical Genetics and Genomics; Ophthalmology and Visual Sciences
- Record Identifier
- 9983979968302771
Metrics
40 Record Views