Developmental downregulation of LIS1 expression limits axonal extension and allows axon pruning
The robust axonal growth and regenerative capacities of young neurons decrease substantially with age. This developmental downregulation of axonal growth may facilitate axonal pruning and neural circuit formation but limits functional recovery following nerve damage. While external factors influenci...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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The Company of Biologists
2017-07-01
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| Series: | Biology Open |
| Subjects: | |
| Online Access: | http://bio.biologists.org/content/6/7/1041 |
| _version_ | 1818865591373529088 |
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| author | Kanako Kumamoto Tokuichi Iguchi Ryuichi Ishida Takuya Uemura Makoto Sato Shinji Hirotsune |
| author_facet | Kanako Kumamoto Tokuichi Iguchi Ryuichi Ishida Takuya Uemura Makoto Sato Shinji Hirotsune |
| author_sort | Kanako Kumamoto |
| collection | DOAJ |
| description | The robust axonal growth and regenerative capacities of young neurons decrease substantially with age. This developmental downregulation of axonal growth may facilitate axonal pruning and neural circuit formation but limits functional recovery following nerve damage. While external factors influencing axonal growth have been extensively investigated, relatively little is known about the intrinsic molecular changes underlying the age-dependent reduction in regeneration capacity. We report that developmental downregulation of LIS1 is responsible for the decreased axonal extension capacity of mature dorsal root ganglion (DRG) neurons. In contrast, exogenous LIS1 expression or endogenous LIS1 augmentation by calpain inhibition restored axonal extension capacity in mature DRG neurons and facilitated regeneration of the damaged sciatic nerve. The insulator protein CTCF suppressed LIS1 expression in mature DRG neurons, and this reduction resulted in excessive accumulation of phosphoactivated GSK-3β at the axon tip, causing failure of the axonal extension. Conversely, sustained LIS1 expression inhibited developmental axon pruning in the mammillary body. Thus, LIS1 regulation may coordinate the balance between axonal growth and pruning during maturation of neuronal circuits. |
| first_indexed | 2024-12-19T10:49:59Z |
| format | Article |
| id | doaj.art-753d756b2bf047f7bb80197f14c398f8 |
| institution | Directory Open Access Journal |
| issn | 2046-6390 |
| language | English |
| last_indexed | 2024-12-19T10:49:59Z |
| publishDate | 2017-07-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Biology Open |
| spelling | doaj.art-753d756b2bf047f7bb80197f14c398f82022-12-21T20:25:03ZengThe Company of BiologistsBiology Open2046-63902017-07-01671041105510.1242/bio.025999025999Developmental downregulation of LIS1 expression limits axonal extension and allows axon pruningKanako Kumamoto0Tokuichi Iguchi1Ryuichi Ishida2Takuya Uemura3Makoto Sato4Shinji Hirotsune5 Department of Genetic Disease Research, Osaka City University, Graduate School of Medicine, Asahi-machi 1-4-3, Abeno, Osaka 545-8585, Japan Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan Department of Genetic Disease Research, Osaka City University, Graduate School of Medicine, Asahi-machi 1-4-3, Abeno, Osaka 545-8585, Japan Department of Orthopaedic Surgery, Osaka City University Graduate School of Medicine, Asahi-machi 1-4-3, Abeno, Osaka 545-8585, Japan Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan Department of Genetic Disease Research, Osaka City University, Graduate School of Medicine, Asahi-machi 1-4-3, Abeno, Osaka 545-8585, Japan The robust axonal growth and regenerative capacities of young neurons decrease substantially with age. This developmental downregulation of axonal growth may facilitate axonal pruning and neural circuit formation but limits functional recovery following nerve damage. While external factors influencing axonal growth have been extensively investigated, relatively little is known about the intrinsic molecular changes underlying the age-dependent reduction in regeneration capacity. We report that developmental downregulation of LIS1 is responsible for the decreased axonal extension capacity of mature dorsal root ganglion (DRG) neurons. In contrast, exogenous LIS1 expression or endogenous LIS1 augmentation by calpain inhibition restored axonal extension capacity in mature DRG neurons and facilitated regeneration of the damaged sciatic nerve. The insulator protein CTCF suppressed LIS1 expression in mature DRG neurons, and this reduction resulted in excessive accumulation of phosphoactivated GSK-3β at the axon tip, causing failure of the axonal extension. Conversely, sustained LIS1 expression inhibited developmental axon pruning in the mammillary body. Thus, LIS1 regulation may coordinate the balance between axonal growth and pruning during maturation of neuronal circuits.http://bio.biologists.org/content/6/7/1041LIS1Axonal transportAxonal extensionPruningNerve degenerationNerve regeneration |
| spellingShingle | Kanako Kumamoto Tokuichi Iguchi Ryuichi Ishida Takuya Uemura Makoto Sato Shinji Hirotsune Developmental downregulation of LIS1 expression limits axonal extension and allows axon pruning Biology Open LIS1 Axonal transport Axonal extension Pruning Nerve degeneration Nerve regeneration |
| title | Developmental downregulation of LIS1 expression limits axonal extension and allows axon pruning |
| title_full | Developmental downregulation of LIS1 expression limits axonal extension and allows axon pruning |
| title_fullStr | Developmental downregulation of LIS1 expression limits axonal extension and allows axon pruning |
| title_full_unstemmed | Developmental downregulation of LIS1 expression limits axonal extension and allows axon pruning |
| title_short | Developmental downregulation of LIS1 expression limits axonal extension and allows axon pruning |
| title_sort | developmental downregulation of lis1 expression limits axonal extension and allows axon pruning |
| topic | LIS1 Axonal transport Axonal extension Pruning Nerve degeneration Nerve regeneration |
| url | http://bio.biologists.org/content/6/7/1041 |
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