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

SS Lin, BH Tzeng, KR Lee, RJH Smith… - Proceedings of the …, 2014 - National Acad Sciences
SS Lin, BH Tzeng, KR Lee, RJH Smith, KP Campbell, CC Chen
Proceedings of the National Academy of Sciences, 2014National Acad Sciences
Intracellular Ca2+ transient is crucial in initiating the differentiation of mesenchymal cells into
chondrocytes, but whether voltage-gated Ca2+ channels are involved remains uncertain.
Here, we show that the T-type voltage-gated Ca2+ 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 …
Intracellular Ca2+ transient is crucial in initiating the differentiation of mesenchymal cells into chondrocytes, but whether voltage-gated Ca2+ channels are involved remains uncertain. Here, we show that the T-type voltage-gated Ca2+ 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 Ca2+ channels and inhibiting calcineurin and suggests that Cav3.2 is responsible for Ca2+ 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, Ca2+ 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 Ca2+ influx via the Cav3.2 T-type Ca2+ channel regulates Sox9 expression through the calcineurin/NFAT signaling pathway during tracheal chondrogenesis.
National Acad Sciences