Cav3.2 T-type calcium channel is required for the NFAT-dependent Sox9 expression in tracheal cartilage

Shin-Shiou Lin; Bing-Hsiean Tzeng; Kuan-Rong Lee; Richard J H Smith; Kevin P Campbell; Chien-Chang Chen

doi:10.1073/pnas.1323112111

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Cav3.2 T-type calcium channel is required for the NFAT-dependent Sox9 expression in tracheal cartilage

Journal article

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Peer reviewed

Cav3.2 T-type calcium channel is required for the NFAT-dependent Sox9 expression in tracheal cartilage

Shin-Shiou Lin, Bing-Hsiean Tzeng, Kuan-Rong Lee, Richard J H Smith, Kevin P Campbell and Chien-Chang Chen

Proceedings of the National Academy of Sciences - PNAS, Vol.111(19), pp.E1990-E1998

05/13/2014

DOI: 10.1073/pnas.1323112111

PMCID: PMC4024911

PMID: 24778262

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Abstract

Intracellular Ca(2+) transient is crucial in initiating the differentiation of mesenchymal cells into chondrocytes, but whether voltage-gated Ca(2+) channels are involved remains uncertain. Here, we show that the T-type voltage-gated Ca(2+) channel Cav3.2 is essential for tracheal chondrogenesis. Mice lacking this channel (Cav3.2(-/-)) show congenital tracheal stenosis because of incomplete formation of cartilaginous tracheal support. Conversely, Cav3.2 overexpression in ATDC5 cells enhances chondrogenesis, which could be blunted by both blocking T-type Ca(2+) channels and inhibiting calcineurin and suggests that Cav3.2 is responsible for Ca(2+) influx during chondrogenesis. Finally, the expression of sex determination region of Y chromosome (SRY)-related high-mobility group-Box gene 9 (Sox9), one of the earliest markers of committed chondrogenic cells, is reduced in Cav3.2(-/-) tracheas. Mechanistically, Ca(2+) influx via Cav3.2 activates the calcineurin/nuclear factor of the activated T-cell (NFAT) signaling pathway, and a previously unidentified NFAT binding site is identified within the mouse Sox9 promoter using a luciferase reporter assay and gel shift and ChIP studies. Our findings define a previously unidentified mechanism that Ca(2+) influx via the Cav3.2 T-type Ca(2+) channel regulates Sox9 expression through the calcineurin/NFAT signaling pathway during tracheal chondrogenesis.

Chondrocytes - cytology

Chondrogenesis - genetics

Male

Mice, 129 Strain

Chondrocytes - physiology

Gene Expression Regulation, Developmental

Cartilage - cytology

Trachea - physiology

Cartilage - physiology

Female

Calcium Channels, T-Type - genetics

SOX9 Transcription Factor - metabolism

Calcium Channels, T-Type - physiology

Cartilage - embryology

Trachea - cytology

NFATC Transcription Factors - metabolism

Cells, Cultured

Trachea - embryology

Mice, Inbred ICR

Mice, Knockout

Chondrogenesis - physiology

Animals

Promoter Regions, Genetic - physiology

Mice

SOX9 Transcription Factor - genetics

Calcineurin - metabolism

Details

Title: Subtitle: Cav3.2 T-type calcium channel is required for the NFAT-dependent Sox9 expression in tracheal cartilage
Creators: Shin-Shiou Lin - Institute of Molecular Medicine, National Tsing Hua University, Hsinchu 30013, Taiwan;Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan
Bing-Hsiean Tzeng - Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan;Division of Cardiovascular Medicine, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan; and
Kuan-Rong Lee - Institute of Molecular Medicine, National Tsing Hua University, Hsinchu 30013, Taiwan
Richard J H Smith - Departments of Otolaryngology, Internal Medicine, Pediatrics, and Molecular Physiology and Biophysics
Kevin P Campbell - Howard Hughes Medical Institute, andDepartments of Molecular Physiology and Biophysics, Neurology, and Internal Medicine, University of Iowa, Iowa City, IA 52242
Chien-Chang Chen - Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan; ccchen@ibms.sinica.edu.tw
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.111(19), pp.E1990-E1998
DOI: 10.1073/pnas.1323112111
PMID: 24778262
PMCID: PMC4024911
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Publisher: National Academy of Sciences; United States
Grant note: Howard Hughes Medical Institute U54 NS053672 / NINDS NIH HHS
Language: English
Date published: 05/13/2014
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Neurology; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Otolaryngology; Internal Medicine
Record Identifier: 9984007167502771

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