CLRN1 is nonessential in the mouse retina but is required for cochlear hair cell development.
Mutations in the CLRN1 gene cause Usher syndrome type 3 (USH3), a human disease characterized by progressive blindness and deafness. Clarin 1, the protein product of CLRN1, is a four-transmembrane protein predicted to be associated with ribbon synapses of photoreceptors and cochlear hair cells, and...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2009-08-01
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| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC2719914?pdf=render |
| _version_ | 1818145346285469696 |
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| author | Scott F Geller Karen I Guerin Meike Visel Aaron Pham Edwin S Lee Amiel A Dror Karen B Avraham Toshinori Hayashi Catherine A Ray Thomas A Reh Olivia Bermingham-McDonogh William J Triffo Shaowen Bao Juha Isosomppi Hanna Västinsalo Eeva-Marja Sankila John G Flannery |
| author_facet | Scott F Geller Karen I Guerin Meike Visel Aaron Pham Edwin S Lee Amiel A Dror Karen B Avraham Toshinori Hayashi Catherine A Ray Thomas A Reh Olivia Bermingham-McDonogh William J Triffo Shaowen Bao Juha Isosomppi Hanna Västinsalo Eeva-Marja Sankila John G Flannery |
| author_sort | Scott F Geller |
| collection | DOAJ |
| description | Mutations in the CLRN1 gene cause Usher syndrome type 3 (USH3), a human disease characterized by progressive blindness and deafness. Clarin 1, the protein product of CLRN1, is a four-transmembrane protein predicted to be associated with ribbon synapses of photoreceptors and cochlear hair cells, and recently demonstrated to be associated with the cytoskeleton. To study Clrn1, we created a Clrn1 knockout (KO) mouse and characterized the histological and functional consequences of Clrn1 deletion in the retina and cochlea. Clrn1 KO mice do not develop a retinal degeneration phenotype, but exhibit progressive loss of sensory hair cells in the cochlea and deterioration of the organ of Corti by 4 months. Hair cell stereocilia in KO animals were longer and disorganized by 4 months, and some Clrn1 KO mice exhibited circling behavior by 5-6 months of age. Clrn1 mRNA expression was localized in the retina using in situ hybridization (ISH), laser capture microdissection (LCM), and RT-PCR. Retinal Clrn1 transcripts were found throughout development and adulthood by RT-PCR, although expression peaked at P7 and declined to undetectable levels in adult retina by ISH. LCM localized Clrn1 transcripts to the retinas inner nuclear layer, and WT levels of retinal Clrn1 expression were observed in photoreceptor-less retinas. Examination of Clrn1 KO mice suggests that CLRN1 is unnecessary in the murine retina but essential for normal cochlear development and function. This may reflect a redundancy in the mouse retina not present in human retina. In contrast to mouse KO models of USH1 and USH2, our data indicate that Clrn1 expression in the retina is restricted to the Müller glia. This is a novel finding, as most retinal degeneration associated proteins are expressed in photoreceptors, not in glia. If CLRN1 expression in humans is comparable to the expression pattern observed in mice, this is the first report of an inner retinal protein that, when mutated, causes retinal degeneration. |
| first_indexed | 2024-12-11T12:02:00Z |
| format | Article |
| id | doaj.art-5b0b5b895c4640a499371880eb763eef |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-12-11T12:02:00Z |
| publishDate | 2009-08-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-5b0b5b895c4640a499371880eb763eef2022-12-22T01:08:04ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042009-08-0158e100060710.1371/journal.pgen.1000607CLRN1 is nonessential in the mouse retina but is required for cochlear hair cell development.Scott F GellerKaren I GuerinMeike ViselAaron PhamEdwin S LeeAmiel A DrorKaren B AvrahamToshinori HayashiCatherine A RayThomas A RehOlivia Bermingham-McDonoghWilliam J TriffoShaowen BaoJuha IsosomppiHanna VästinsaloEeva-Marja SankilaJohn G FlanneryMutations in the CLRN1 gene cause Usher syndrome type 3 (USH3), a human disease characterized by progressive blindness and deafness. Clarin 1, the protein product of CLRN1, is a four-transmembrane protein predicted to be associated with ribbon synapses of photoreceptors and cochlear hair cells, and recently demonstrated to be associated with the cytoskeleton. To study Clrn1, we created a Clrn1 knockout (KO) mouse and characterized the histological and functional consequences of Clrn1 deletion in the retina and cochlea. Clrn1 KO mice do not develop a retinal degeneration phenotype, but exhibit progressive loss of sensory hair cells in the cochlea and deterioration of the organ of Corti by 4 months. Hair cell stereocilia in KO animals were longer and disorganized by 4 months, and some Clrn1 KO mice exhibited circling behavior by 5-6 months of age. Clrn1 mRNA expression was localized in the retina using in situ hybridization (ISH), laser capture microdissection (LCM), and RT-PCR. Retinal Clrn1 transcripts were found throughout development and adulthood by RT-PCR, although expression peaked at P7 and declined to undetectable levels in adult retina by ISH. LCM localized Clrn1 transcripts to the retinas inner nuclear layer, and WT levels of retinal Clrn1 expression were observed in photoreceptor-less retinas. Examination of Clrn1 KO mice suggests that CLRN1 is unnecessary in the murine retina but essential for normal cochlear development and function. This may reflect a redundancy in the mouse retina not present in human retina. In contrast to mouse KO models of USH1 and USH2, our data indicate that Clrn1 expression in the retina is restricted to the Müller glia. This is a novel finding, as most retinal degeneration associated proteins are expressed in photoreceptors, not in glia. If CLRN1 expression in humans is comparable to the expression pattern observed in mice, this is the first report of an inner retinal protein that, when mutated, causes retinal degeneration.http://europepmc.org/articles/PMC2719914?pdf=render |
| spellingShingle | Scott F Geller Karen I Guerin Meike Visel Aaron Pham Edwin S Lee Amiel A Dror Karen B Avraham Toshinori Hayashi Catherine A Ray Thomas A Reh Olivia Bermingham-McDonogh William J Triffo Shaowen Bao Juha Isosomppi Hanna Västinsalo Eeva-Marja Sankila John G Flannery CLRN1 is nonessential in the mouse retina but is required for cochlear hair cell development. PLoS Genetics |
| title | CLRN1 is nonessential in the mouse retina but is required for cochlear hair cell development. |
| title_full | CLRN1 is nonessential in the mouse retina but is required for cochlear hair cell development. |
| title_fullStr | CLRN1 is nonessential in the mouse retina but is required for cochlear hair cell development. |
| title_full_unstemmed | CLRN1 is nonessential in the mouse retina but is required for cochlear hair cell development. |
| title_short | CLRN1 is nonessential in the mouse retina but is required for cochlear hair cell development. |
| title_sort | clrn1 is nonessential in the mouse retina but is required for cochlear hair cell development |
| url | http://europepmc.org/articles/PMC2719914?pdf=render |
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