The <i>MCPH7</i> Gene Product STIL Is Essential for Dendritic Spine Formation
Dendritic spine formation/maintenance is highly dependent on actin cytoskeletal dynamics, which is regulated by small GTPases Rac1 and Cdc42 through their downstream p21-activated kinase/LIM-kinase-I/cofilin pathway. ARHGEF7, also known as ß-PIX, is a guanine nucleotide exchange factor for Rac1 and...
Saved in:
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-01-01
|
| Series: | Cells |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4409/14/2/62 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832588838471467008 |
|---|---|
| author | Tohru Matsuki Hidenori Tabata Masashi Ueda Hideaki Ito Koh-ichi Nagata Yumi Tsuneura Shima Eda Kenji Kasai Atsuo Nakayama |
| author_facet | Tohru Matsuki Hidenori Tabata Masashi Ueda Hideaki Ito Koh-ichi Nagata Yumi Tsuneura Shima Eda Kenji Kasai Atsuo Nakayama |
| author_sort | Tohru Matsuki |
| collection | DOAJ |
| description | Dendritic spine formation/maintenance is highly dependent on actin cytoskeletal dynamics, which is regulated by small GTPases Rac1 and Cdc42 through their downstream p21-activated kinase/LIM-kinase-I/cofilin pathway. ARHGEF7, also known as ß-PIX, is a guanine nucleotide exchange factor for Rac1 and Cdc42, thereby activating Rac1/Cdc42 and the downstream pathway, leading to the upregulation of spine formation/maintenance. We found that STIL, one of the primary microcephaly gene products, is associated with ARHGEF7 in dendritic spines and that knockdown of <i>Stil</i> resulted in a significant reduction in dendritic spines in neurons both in vitro and in vivo. Rescue experiments indicated that the STIL requirement for spine formation/maintenance depended on its coiled coil domain that mediates the association with ARHGEF7. The overexpression of Rac1/Cdc42 compensated for the spine reduction caused by STIL knockdown. FRET experiments showed that Rac activation is impaired in STIL knockdown neurons. Chemical long-term potentiation, which triggers Rac activation, promoted STIL accumulation in the spine and its association with ARHGEF7. The dynamics of these proteins further supported their coordinated involvement in spine formation/maintenance. Based on these findings, we concluded that the centrosomal protein STIL is a novel regulatory factor essential for spine formation/maintenance by activating Rac and its downstream pathway, possibly through the association with ARHGEF7. |
| format | Article |
| id | doaj-art-5facd62964a5438da862d5dfdb81d3d5 |
| institution | Kabale University |
| issn | 2073-4409 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj-art-5facd62964a5438da862d5dfdb81d3d52025-01-24T13:26:32ZengMDPI AGCells2073-44092025-01-011426210.3390/cells14020062The <i>MCPH7</i> Gene Product STIL Is Essential for Dendritic Spine FormationTohru Matsuki0Hidenori Tabata1Masashi Ueda2Hideaki Ito3Koh-ichi Nagata4Yumi Tsuneura5Shima Eda6Kenji Kasai7Atsuo Nakayama8Department of Cellular Pathology, Institute for Developmental Research, Aichi Developmental Disability Center, Kasugai 480-0392, Aichi, JapanDepartment of Molecular Neurobiology, Institute for Developmental Research, Aichi Developmental Disability Center, Kasugai 480-0392, Aichi, JapanDepartment of Cellular Pathology, Institute for Developmental Research, Aichi Developmental Disability Center, Kasugai 480-0392, Aichi, JapanDepartment of Pathology, Aichi Medical University School of Medicine, Nagakute 480-1195, Aichi, JapanDepartment of Molecular Neurobiology, Institute for Developmental Research, Aichi Developmental Disability Center, Kasugai 480-0392, Aichi, JapanDepartment of Cellular Pathology, Institute for Developmental Research, Aichi Developmental Disability Center, Kasugai 480-0392, Aichi, JapanDepartment of Cellular Pathology, Institute for Developmental Research, Aichi Developmental Disability Center, Kasugai 480-0392, Aichi, JapanDepartment of Pathology, Aichi Medical University School of Medicine, Nagakute 480-1195, Aichi, JapanDepartment of Cellular Pathology, Institute for Developmental Research, Aichi Developmental Disability Center, Kasugai 480-0392, Aichi, JapanDendritic spine formation/maintenance is highly dependent on actin cytoskeletal dynamics, which is regulated by small GTPases Rac1 and Cdc42 through their downstream p21-activated kinase/LIM-kinase-I/cofilin pathway. ARHGEF7, also known as ß-PIX, is a guanine nucleotide exchange factor for Rac1 and Cdc42, thereby activating Rac1/Cdc42 and the downstream pathway, leading to the upregulation of spine formation/maintenance. We found that STIL, one of the primary microcephaly gene products, is associated with ARHGEF7 in dendritic spines and that knockdown of <i>Stil</i> resulted in a significant reduction in dendritic spines in neurons both in vitro and in vivo. Rescue experiments indicated that the STIL requirement for spine formation/maintenance depended on its coiled coil domain that mediates the association with ARHGEF7. The overexpression of Rac1/Cdc42 compensated for the spine reduction caused by STIL knockdown. FRET experiments showed that Rac activation is impaired in STIL knockdown neurons. Chemical long-term potentiation, which triggers Rac activation, promoted STIL accumulation in the spine and its association with ARHGEF7. The dynamics of these proteins further supported their coordinated involvement in spine formation/maintenance. Based on these findings, we concluded that the centrosomal protein STIL is a novel regulatory factor essential for spine formation/maintenance by activating Rac and its downstream pathway, possibly through the association with ARHGEF7.https://www.mdpi.com/2073-4409/14/2/62MCPH7STILdendritic spineARHGEF7Rac1Cdc42 |
| spellingShingle | Tohru Matsuki Hidenori Tabata Masashi Ueda Hideaki Ito Koh-ichi Nagata Yumi Tsuneura Shima Eda Kenji Kasai Atsuo Nakayama The <i>MCPH7</i> Gene Product STIL Is Essential for Dendritic Spine Formation Cells MCPH7 STIL dendritic spine ARHGEF7 Rac1 Cdc42 |
| title | The <i>MCPH7</i> Gene Product STIL Is Essential for Dendritic Spine Formation |
| title_full | The <i>MCPH7</i> Gene Product STIL Is Essential for Dendritic Spine Formation |
| title_fullStr | The <i>MCPH7</i> Gene Product STIL Is Essential for Dendritic Spine Formation |
| title_full_unstemmed | The <i>MCPH7</i> Gene Product STIL Is Essential for Dendritic Spine Formation |
| title_short | The <i>MCPH7</i> Gene Product STIL Is Essential for Dendritic Spine Formation |
| title_sort | i mcph7 i gene product stil is essential for dendritic spine formation |
| topic | MCPH7 STIL dendritic spine ARHGEF7 Rac1 Cdc42 |
| url | https://www.mdpi.com/2073-4409/14/2/62 |
| work_keys_str_mv | AT tohrumatsuki theimcph7igeneproductstilisessentialfordendriticspineformation AT hidenoritabata theimcph7igeneproductstilisessentialfordendriticspineformation AT masashiueda theimcph7igeneproductstilisessentialfordendriticspineformation AT hideakiito theimcph7igeneproductstilisessentialfordendriticspineformation AT kohichinagata theimcph7igeneproductstilisessentialfordendriticspineformation AT yumitsuneura theimcph7igeneproductstilisessentialfordendriticspineformation AT shimaeda theimcph7igeneproductstilisessentialfordendriticspineformation AT kenjikasai theimcph7igeneproductstilisessentialfordendriticspineformation AT atsuonakayama theimcph7igeneproductstilisessentialfordendriticspineformation AT tohrumatsuki imcph7igeneproductstilisessentialfordendriticspineformation AT hidenoritabata imcph7igeneproductstilisessentialfordendriticspineformation AT masashiueda imcph7igeneproductstilisessentialfordendriticspineformation AT hideakiito imcph7igeneproductstilisessentialfordendriticspineformation AT kohichinagata imcph7igeneproductstilisessentialfordendriticspineformation AT yumitsuneura imcph7igeneproductstilisessentialfordendriticspineformation AT shimaeda imcph7igeneproductstilisessentialfordendriticspineformation AT kenjikasai imcph7igeneproductstilisessentialfordendriticspineformation AT atsuonakayama imcph7igeneproductstilisessentialfordendriticspineformation |