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Proc Natl Acad Sci U S A. 2019 Oct 22;116(43):21592-21601. doi: 10.1073/pnas.1908981116. Epub 2019 Oct 7.

L-type voltage-gated Ca2+ channel CaV1.2 regulates chondrogenesis during limb development.

Author information

1
Department of Genetics, Harvard Medical School, Boston, MA 02115.
2
Allen Discovery Center at Tufts University, Tufts University, Medford, MA 02155.
3
Department of Biology, Tufts University, Medford, MA 02155.
4
Department of Genetics, Harvard Medical School, Boston, MA 02115; tabin@genetics.med.harvard.edu.

Abstract

All cells, including nonexcitable cells, maintain a discrete transmembrane potential (V mem), and have the capacity to modulate V mem and respond to their own and neighbors' changes in V mem Spatiotemporal variations have been described in developing embryonic tissues and in some cases have been implicated in influencing developmental processes. Yet, how such changes in V mem are converted into intracellular inputs that in turn regulate developmental gene expression and coordinate patterned tissue formation, has remained elusive. Here we document that the V mem of limb mesenchyme switches from a hyperpolarized to depolarized state during early chondrocyte differentiation. This change in V mem increases intracellular Ca2+ signaling through Ca2+ influx, via CaV1.2, 1 of L-type voltage-gated Ca2+ channels (VGCCs). We find that CaV1.2 activity is essential for chondrogenesis in the developing limbs. Pharmacological inhibition by an L-type VGCC specific blocker, or limb-specific deletion of CaV1.2, down-regulates expression of genes essential for chondrocyte differentiation, including Sox9, Col2a1, and Agc1, and thus disturbs proper cartilage formation. The Ca2+-dependent transcription factor NFATc1, which is a known major transducer of intracellular Ca2+ signaling, partly rescues Sox9 expression. These data reveal instructive roles of CaV1.2 in limb development, and more generally expand our understanding of how modulation of membrane potential is used as a mechanism of developmental regulation.

KEYWORDS:

calcium channel; chondrogenesis; limb development; membrane potential

PMID:
31591237
PMCID:
PMC6815189
[Available on 2020-04-07]
DOI:
10.1073/pnas.1908981116

Conflict of interest statement

The authors declare no competing interest.

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