The T‐Type Calcium Channel CACNA1H is Required for Smooth Muscle Cytoskeletal Organization During Tracheal Tubulogenesis
Abstract Abnormalities of tracheal smooth muscle (SM) formation are associated with several clinical disorders including tracheal stenosis and tracheomalacia. However, the cellular and molecular mechanisms underlying tracheal SM formation remain poorly understood. Here, it is shown that the T‐type c...
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2024-11-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202308622 |
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| author | Ziying Liu Chunyan Lu Li Ma Changjiang Li Haiyun Luo Yiqi Liu Xinyuan Liu Haiqing Li Yachao Cui Jiahang Zeng Natalia Bottasso‐Arias Debora Sinner Le Li Jian Wang Didier Y. R. Stainier Wenguang Yin |
| author_facet | Ziying Liu Chunyan Lu Li Ma Changjiang Li Haiyun Luo Yiqi Liu Xinyuan Liu Haiqing Li Yachao Cui Jiahang Zeng Natalia Bottasso‐Arias Debora Sinner Le Li Jian Wang Didier Y. R. Stainier Wenguang Yin |
| author_sort | Ziying Liu |
| collection | DOAJ |
| description | Abstract Abnormalities of tracheal smooth muscle (SM) formation are associated with several clinical disorders including tracheal stenosis and tracheomalacia. However, the cellular and molecular mechanisms underlying tracheal SM formation remain poorly understood. Here, it is shown that the T‐type calcium channel CACNA1H is a novel regulator of tracheal SM formation and contraction. Cacna1h in an ethylnitrosourea forward genetic screen for regulators of respiratory disease using the mouse as a model is identified. Cacna1h mutants exhibit tracheal stenosis, disorganized SM and compromised tracheal contraction. CACNA1H is essential to maintain actin polymerization, which is required for tracheal SM organization and tube formation. This process appears to be partially mediated through activation of the actin regulator RhoA, as pharmacological increase of RhoA activity ameliorates the Cacna1h‐mutant trachea phenotypes. Analysis of human tracheal tissues indicates that a decrease in CACNA1H protein levels is associated with congenital tracheostenosis. These results provide insight into the role for the T‐type calcium channel in cytoskeletal organization and SM formation during tracheal tube formation and suggest novel targets for congenital tracheostenosis intervention. |
| format | Article |
| id | doaj-art-8e921e1b85084c32a1f45689b90f74a4 |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-8e921e1b85084c32a1f45689b90f74a42024-11-27T11:21:53ZengWileyAdvanced Science2198-38442024-11-011144n/an/a10.1002/advs.202308622The T‐Type Calcium Channel CACNA1H is Required for Smooth Muscle Cytoskeletal Organization During Tracheal TubulogenesisZiying Liu0Chunyan Lu1Li Ma2Changjiang Li3Haiyun Luo4Yiqi Liu5Xinyuan Liu6Haiqing Li7Yachao Cui8Jiahang Zeng9Natalia Bottasso‐Arias10Debora Sinner11Le Li12Jian Wang13Didier Y. R. Stainier14Wenguang Yin15State Key Laboratory of Respiratory Disease National Clinical Research Center for Respiratory Disease Guangzhou Institute of Respiratory Health the First Affiliated Hospital of Guangzhou Medical University Guangzhou Guangdong 510182 P. R. ChinaState Key Laboratory of Respiratory Disease National Clinical Research Center for Respiratory Disease Guangzhou Institute of Respiratory Health the First Affiliated Hospital of Guangzhou Medical University Guangzhou Guangdong 510182 P. R. ChinaHeart center & Department of Pediatric Surgery Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease Guangzhou Women and Children's Medical Center Guangzhou Medical University Guangzhou Guangdong 510623 P. R. ChinaState Key Laboratory of Respiratory Disease National Clinical Research Center for Respiratory Disease Guangzhou Institute of Respiratory Health the First Affiliated Hospital of Guangzhou Medical University Guangzhou Guangdong 510182 P. R. ChinaState Key Laboratory of Respiratory Disease National Clinical Research Center for Respiratory Disease Guangzhou Institute of Respiratory Health the First Affiliated Hospital of Guangzhou Medical University Guangzhou Guangdong 510182 P. R. ChinaState Key Laboratory of Respiratory Disease National Clinical Research Center for Respiratory Disease Guangzhou Institute of Respiratory Health the First Affiliated Hospital of Guangzhou Medical University Guangzhou Guangdong 510182 P. R. ChinaState Key Laboratory of Respiratory Disease National Clinical Research Center for Respiratory Disease Guangzhou Institute of Respiratory Health the First Affiliated Hospital of Guangzhou Medical University Guangzhou Guangdong 510182 P. R. ChinaState Key Laboratory of Respiratory Disease National Clinical Research Center for Respiratory Disease Guangzhou Institute of Respiratory Health the First Affiliated Hospital of Guangzhou Medical University Guangzhou Guangdong 510182 P. R. ChinaState Key Laboratory of Respiratory Disease National Clinical Research Center for Respiratory Disease Guangzhou Institute of Respiratory Health the First Affiliated Hospital of Guangzhou Medical University Guangzhou Guangdong 510182 P. R. ChinaDepartment of Thoracic Surgery Guangzhou Women and Children's Medical Center Guangzhou Medical University Guangzhou 510623 P. R. ChinaDivision of Neonatology and Pulmonary Biology CCHMC College of Medicine University of Cincinnati Cincinnati OH 45221 USADivision of Neonatology and Pulmonary Biology CCHMC College of Medicine University of Cincinnati Cincinnati OH 45221 USADepartment of Thoracic Surgery Guangzhou Women and Children's Medical Center Guangzhou Medical University Guangzhou 510623 P. R. ChinaState Key Laboratory of Respiratory Disease National Clinical Research Center for Respiratory Disease Guangzhou Institute of Respiratory Health the First Affiliated Hospital of Guangzhou Medical University Guangzhou Guangdong 510182 P. R. ChinaDepartment of Developmental Genetics Max Planck Institute for Heart and Lung Research Member of the German Center for Lung Research (DZL) 61231 Bad Nauheim GermanyState Key Laboratory of Respiratory Disease National Clinical Research Center for Respiratory Disease Guangzhou Institute of Respiratory Health the First Affiliated Hospital of Guangzhou Medical University Guangzhou Guangdong 510182 P. R. ChinaAbstract Abnormalities of tracheal smooth muscle (SM) formation are associated with several clinical disorders including tracheal stenosis and tracheomalacia. However, the cellular and molecular mechanisms underlying tracheal SM formation remain poorly understood. Here, it is shown that the T‐type calcium channel CACNA1H is a novel regulator of tracheal SM formation and contraction. Cacna1h in an ethylnitrosourea forward genetic screen for regulators of respiratory disease using the mouse as a model is identified. Cacna1h mutants exhibit tracheal stenosis, disorganized SM and compromised tracheal contraction. CACNA1H is essential to maintain actin polymerization, which is required for tracheal SM organization and tube formation. This process appears to be partially mediated through activation of the actin regulator RhoA, as pharmacological increase of RhoA activity ameliorates the Cacna1h‐mutant trachea phenotypes. Analysis of human tracheal tissues indicates that a decrease in CACNA1H protein levels is associated with congenital tracheostenosis. These results provide insight into the role for the T‐type calcium channel in cytoskeletal organization and SM formation during tracheal tube formation and suggest novel targets for congenital tracheostenosis intervention.https://doi.org/10.1002/advs.202308622Cacna1hcytoskeletonRhoAsmooth muscletracheal stenosis |
| spellingShingle | Ziying Liu Chunyan Lu Li Ma Changjiang Li Haiyun Luo Yiqi Liu Xinyuan Liu Haiqing Li Yachao Cui Jiahang Zeng Natalia Bottasso‐Arias Debora Sinner Le Li Jian Wang Didier Y. R. Stainier Wenguang Yin The T‐Type Calcium Channel CACNA1H is Required for Smooth Muscle Cytoskeletal Organization During Tracheal Tubulogenesis Advanced Science Cacna1h cytoskeleton RhoA smooth muscle tracheal stenosis |
| title | The T‐Type Calcium Channel CACNA1H is Required for Smooth Muscle Cytoskeletal Organization During Tracheal Tubulogenesis |
| title_full | The T‐Type Calcium Channel CACNA1H is Required for Smooth Muscle Cytoskeletal Organization During Tracheal Tubulogenesis |
| title_fullStr | The T‐Type Calcium Channel CACNA1H is Required for Smooth Muscle Cytoskeletal Organization During Tracheal Tubulogenesis |
| title_full_unstemmed | The T‐Type Calcium Channel CACNA1H is Required for Smooth Muscle Cytoskeletal Organization During Tracheal Tubulogenesis |
| title_short | The T‐Type Calcium Channel CACNA1H is Required for Smooth Muscle Cytoskeletal Organization During Tracheal Tubulogenesis |
| title_sort | t type calcium channel cacna1h is required for smooth muscle cytoskeletal organization during tracheal tubulogenesis |
| topic | Cacna1h cytoskeleton RhoA smooth muscle tracheal stenosis |
| url | https://doi.org/10.1002/advs.202308622 |
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