Bap1/SMN axis in Dpp4+ skeletal muscle mesenchymal cells regulates the neuromuscular system
The survival of motor neuron (SMN) protein is a major component of the pre-mRNA splicing machinery and is required for RNA metabolism. Although SMN has been considered a fundamental gene for the central nervous system, due to its relationship with neuromuscular diseases, such as spinal muscular atro...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2022-05-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.158380 |
| _version_ | 1818242209918484480 |
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| author | Ji-Hoon Kim Jong-Seol Kang Kyusang Yoo Jinguk Jeong Inkuk Park Jong Ho Park Joonwoo Rhee Shin Jeon Young-Woo Jo Sang-Hyeon Hann Minji Seo Seungtae Moon Soo-Jong Um Rho Hyun Seong Young-Yun Kong |
| author_facet | Ji-Hoon Kim Jong-Seol Kang Kyusang Yoo Jinguk Jeong Inkuk Park Jong Ho Park Joonwoo Rhee Shin Jeon Young-Woo Jo Sang-Hyeon Hann Minji Seo Seungtae Moon Soo-Jong Um Rho Hyun Seong Young-Yun Kong |
| author_sort | Ji-Hoon Kim |
| collection | DOAJ |
| description | The survival of motor neuron (SMN) protein is a major component of the pre-mRNA splicing machinery and is required for RNA metabolism. Although SMN has been considered a fundamental gene for the central nervous system, due to its relationship with neuromuscular diseases, such as spinal muscular atrophy, recent studies have also revealed the requirement of SMN in non-neuronal cells in the peripheral regions. Here, we report that the fibro-adipogenic progenitor subpopulation expressing Dpp4 (Dpp4+ FAPs) is required for the neuromuscular system. Furthermore, we also reveal that BRCA1-associated protein-1 (Bap1) is crucial for the stabilization of SMN in FAPs by preventing its ubiquitination-dependent degradation. Inactivation of Bap1 in FAPs decreased SMN levels and accompanied degeneration of the neuromuscular junction, leading to loss of motor neurons and muscle atrophy. Overexpression of the ubiquitination-resistant SMN variant, SMNK186R, in Bap1-null FAPs completely prevented neuromuscular degeneration. In addition, transplantation of Dpp4+ FAPs, but not Dpp4– FAPs, completely rescued neuromuscular defects. Our data reveal the crucial role of Bap1-mediated SMN stabilization in Dpp4+ FAPs for the neuromuscular system and provide the possibility of cell-based therapeutics to treat neuromuscular diseases. |
| first_indexed | 2024-12-12T13:41:36Z |
| format | Article |
| id | doaj.art-a3c7d5a5a347457788381a2e9bf92ff5 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-12-12T13:41:36Z |
| publishDate | 2022-05-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-a3c7d5a5a347457788381a2e9bf92ff52022-12-22T00:22:48ZengAmerican Society for Clinical investigationJCI Insight2379-37082022-05-01710Bap1/SMN axis in Dpp4+ skeletal muscle mesenchymal cells regulates the neuromuscular systemJi-Hoon KimJong-Seol KangKyusang YooJinguk JeongInkuk ParkJong Ho ParkJoonwoo RheeShin JeonYoung-Woo JoSang-Hyeon HannMinji SeoSeungtae MoonSoo-Jong UmRho Hyun SeongYoung-Yun KongThe survival of motor neuron (SMN) protein is a major component of the pre-mRNA splicing machinery and is required for RNA metabolism. Although SMN has been considered a fundamental gene for the central nervous system, due to its relationship with neuromuscular diseases, such as spinal muscular atrophy, recent studies have also revealed the requirement of SMN in non-neuronal cells in the peripheral regions. Here, we report that the fibro-adipogenic progenitor subpopulation expressing Dpp4 (Dpp4+ FAPs) is required for the neuromuscular system. Furthermore, we also reveal that BRCA1-associated protein-1 (Bap1) is crucial for the stabilization of SMN in FAPs by preventing its ubiquitination-dependent degradation. Inactivation of Bap1 in FAPs decreased SMN levels and accompanied degeneration of the neuromuscular junction, leading to loss of motor neurons and muscle atrophy. Overexpression of the ubiquitination-resistant SMN variant, SMNK186R, in Bap1-null FAPs completely prevented neuromuscular degeneration. In addition, transplantation of Dpp4+ FAPs, but not Dpp4– FAPs, completely rescued neuromuscular defects. Our data reveal the crucial role of Bap1-mediated SMN stabilization in Dpp4+ FAPs for the neuromuscular system and provide the possibility of cell-based therapeutics to treat neuromuscular diseases.https://doi.org/10.1172/jci.insight.158380Cell biologyMuscle biology |
| spellingShingle | Ji-Hoon Kim Jong-Seol Kang Kyusang Yoo Jinguk Jeong Inkuk Park Jong Ho Park Joonwoo Rhee Shin Jeon Young-Woo Jo Sang-Hyeon Hann Minji Seo Seungtae Moon Soo-Jong Um Rho Hyun Seong Young-Yun Kong Bap1/SMN axis in Dpp4+ skeletal muscle mesenchymal cells regulates the neuromuscular system JCI Insight Cell biology Muscle biology |
| title | Bap1/SMN axis in Dpp4+ skeletal muscle mesenchymal cells regulates the neuromuscular system |
| title_full | Bap1/SMN axis in Dpp4+ skeletal muscle mesenchymal cells regulates the neuromuscular system |
| title_fullStr | Bap1/SMN axis in Dpp4+ skeletal muscle mesenchymal cells regulates the neuromuscular system |
| title_full_unstemmed | Bap1/SMN axis in Dpp4+ skeletal muscle mesenchymal cells regulates the neuromuscular system |
| title_short | Bap1/SMN axis in Dpp4+ skeletal muscle mesenchymal cells regulates the neuromuscular system |
| title_sort | bap1 smn axis in dpp4 skeletal muscle mesenchymal cells regulates the neuromuscular system |
| topic | Cell biology Muscle biology |
| url | https://doi.org/10.1172/jci.insight.158380 |
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