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Proc Natl Acad Sci U S A. 2014 May 13;111(19):E1990-8. doi: 10.1073/pnas.1323112111. Epub 2014 Apr 28.

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

Author information

1
Institute of Molecular Medicine, National Tsing Hua University, Hsinchu 30013, Taiwan;Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan;
2
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.
3
Institute of Molecular Medicine, National Tsing Hua University, Hsinchu 30013, Taiwan;
4
Departments of Otolaryngology, Internal Medicine, Pediatrics, and Molecular Physiology and Biophysics.
5
Howard Hughes Medical Institute, andDepartments of Molecular Physiology and Biophysics, Neurology, and Internal Medicine, University of Iowa, Iowa City, IA 52242.
6
Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan; ccchen@ibms.sinica.edu.tw.

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.

PMID:
24778262
PMCID:
PMC4024911
DOI:
10.1073/pnas.1323112111
[Indexed for MEDLINE]
Free PMC Article

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