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Molecular characterization of MAP9 in the photoreceptor sensory cilia as a modifier in canine RPGRIP1-associated cone-rod dystrophy
Photoreceptors possess a highly specialized primary cilium containing expanded ciliary membrane discs called the outer segment. The photoreceptor cilium is essential for the maintenance of the outer segment, and pathogenic variants in more than 50 cilia-related genes have been identified as causing...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2023
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10464610/ https://www.ncbi.nlm.nih.gov/pubmed/37650070 http://dx.doi.org/10.3389/fncel.2023.1226603 |
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author | Takahashi, Kei Kwok, Jennifer C. Sato, Yu Aguirre, Gustavo D. Miyadera, Keiko |
author_facet | Takahashi, Kei Kwok, Jennifer C. Sato, Yu Aguirre, Gustavo D. Miyadera, Keiko |
author_sort | Takahashi, Kei |
collection | PubMed |
description | Photoreceptors possess a highly specialized primary cilium containing expanded ciliary membrane discs called the outer segment. The photoreceptor cilium is essential for the maintenance of the outer segment, and pathogenic variants in more than 50 cilia-related genes have been identified as causing non-syndromic inherited retinal diseases in patients. The retinitis pigmentosa GTPase regulator interacting protein 1 (RPGRIP1) is a structural protein localized to the photoreceptor cilium and biallelic RPGRIP1 variants have been associated with non-syndromic human inherited retinal diseases. In a canine cone-rod dystrophy model, a naturally occurring 44-bp exonic insertion in RPGRIP1 (RPGRIP1(ins44/ins44)) is the primary disease locus while an additional homozygous variant in MAP9 (microtubule associated protein 9) (MAP9(aff/aff)) acts as a modifier associated with early disease onset. MAP9 was originally identified as a microtubule-binding protein stabilizing microtubule structure during both mitosis and interphase in human cell lines. However, the roles of MAP9 in primary cilia, including photoreceptor neurosensory cilia, have not been well understood. Hence, we characterized the pathogenic phenotypes associated with homozygous MAP9 variant, and investigated the molecular function of MAP9 in primary cilia using the RPGRIP1-associated oligogenic canine cone-rod dystrophy model as well as cultured cells. Both functionally and structurally, the RPGRIP1(ins44/ins44) MAP9(aff/aff) retina exhibited progressive cone photoreceptor degeneration starting earlier than the retina affected by RPGRIP1(ins44/ins44) alone. Based on immunostaining of canine retinal sections and cultured cells, we found that MAP9 is prominently localized in the basal body of primary cilia and played an important role in maintaining the structure of ciliary microtubule axoneme. These findings suggest that the affected MAP9, together with mutant RPGRIP1, is deprived of critical roles in cilia organization and maintenance resulting in altered cilia structure and function giving rise to early onset and accelerated disease progression in the RPGRIP1(ins44/ins44) MAP9(aff/aff) double homozygote cone-rod dystrophy canine model. |
format | Online Article Text |
id | pubmed-10464610 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-104646102023-08-30 Molecular characterization of MAP9 in the photoreceptor sensory cilia as a modifier in canine RPGRIP1-associated cone-rod dystrophy Takahashi, Kei Kwok, Jennifer C. Sato, Yu Aguirre, Gustavo D. Miyadera, Keiko Front Cell Neurosci Neuroscience Photoreceptors possess a highly specialized primary cilium containing expanded ciliary membrane discs called the outer segment. The photoreceptor cilium is essential for the maintenance of the outer segment, and pathogenic variants in more than 50 cilia-related genes have been identified as causing non-syndromic inherited retinal diseases in patients. The retinitis pigmentosa GTPase regulator interacting protein 1 (RPGRIP1) is a structural protein localized to the photoreceptor cilium and biallelic RPGRIP1 variants have been associated with non-syndromic human inherited retinal diseases. In a canine cone-rod dystrophy model, a naturally occurring 44-bp exonic insertion in RPGRIP1 (RPGRIP1(ins44/ins44)) is the primary disease locus while an additional homozygous variant in MAP9 (microtubule associated protein 9) (MAP9(aff/aff)) acts as a modifier associated with early disease onset. MAP9 was originally identified as a microtubule-binding protein stabilizing microtubule structure during both mitosis and interphase in human cell lines. However, the roles of MAP9 in primary cilia, including photoreceptor neurosensory cilia, have not been well understood. Hence, we characterized the pathogenic phenotypes associated with homozygous MAP9 variant, and investigated the molecular function of MAP9 in primary cilia using the RPGRIP1-associated oligogenic canine cone-rod dystrophy model as well as cultured cells. Both functionally and structurally, the RPGRIP1(ins44/ins44) MAP9(aff/aff) retina exhibited progressive cone photoreceptor degeneration starting earlier than the retina affected by RPGRIP1(ins44/ins44) alone. Based on immunostaining of canine retinal sections and cultured cells, we found that MAP9 is prominently localized in the basal body of primary cilia and played an important role in maintaining the structure of ciliary microtubule axoneme. These findings suggest that the affected MAP9, together with mutant RPGRIP1, is deprived of critical roles in cilia organization and maintenance resulting in altered cilia structure and function giving rise to early onset and accelerated disease progression in the RPGRIP1(ins44/ins44) MAP9(aff/aff) double homozygote cone-rod dystrophy canine model. Frontiers Media S.A. 2023-08-15 /pmc/articles/PMC10464610/ /pubmed/37650070 http://dx.doi.org/10.3389/fncel.2023.1226603 Text en Copyright © 2023 Takahashi, Kwok, Sato, Aguirre and Miyadera. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Neuroscience Takahashi, Kei Kwok, Jennifer C. Sato, Yu Aguirre, Gustavo D. Miyadera, Keiko Molecular characterization of MAP9 in the photoreceptor sensory cilia as a modifier in canine RPGRIP1-associated cone-rod dystrophy |
title | Molecular characterization of MAP9 in the photoreceptor sensory cilia as a modifier in canine RPGRIP1-associated cone-rod dystrophy |
title_full | Molecular characterization of MAP9 in the photoreceptor sensory cilia as a modifier in canine RPGRIP1-associated cone-rod dystrophy |
title_fullStr | Molecular characterization of MAP9 in the photoreceptor sensory cilia as a modifier in canine RPGRIP1-associated cone-rod dystrophy |
title_full_unstemmed | Molecular characterization of MAP9 in the photoreceptor sensory cilia as a modifier in canine RPGRIP1-associated cone-rod dystrophy |
title_short | Molecular characterization of MAP9 in the photoreceptor sensory cilia as a modifier in canine RPGRIP1-associated cone-rod dystrophy |
title_sort | molecular characterization of map9 in the photoreceptor sensory cilia as a modifier in canine rpgrip1-associated cone-rod dystrophy |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10464610/ https://www.ncbi.nlm.nih.gov/pubmed/37650070 http://dx.doi.org/10.3389/fncel.2023.1226603 |
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