부산대학교 도서관

All cells, including nonexcitable cells, maintain a discrete transmembrane potential ([V.sub.mem]), and have the capacity to modulate [V.sub.mem] and respond to their own and neighbors' changes in [V.sub.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.sub.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.sub.mem] of limb mesenchyme switches from a hyperpolarized to depolarized state during early chondrocyte differentiation. This change in [V.sub.mem] increases intracellular [Ca.sup.2+] signaling through [Ca.sup.2+] influx, via [Ca.sub.v]1.2, 1 of L-type voltage-gated [Ca.sup.2+] channels (VGCCs). We find that [Ca.sub.v]1.2 activity is essential for chondrogenesis in the developing limbs. Pharmacological inhibition by an L-type VGCC specific blocker, or limb-specific deletion of [Ca.sub.v]1.2, down-regulates expression of genes essential for chondrocyte differentiation, including Sox9, Col2a1, and Agc1, and thus disturbs proper cartilage formation. The [Ca.sup.2+]-dependent transcription factor NFATcl, which is a known major transducer of intracellular [Ca.sup.2+] signaling, partly rescues Sox9 expression. These data reveal instructive roles of [Ca.sub.v]1.2 in limb development, and more generally expand our understanding of how modulation of membrane potential is used as a mechanism of developmental regulation. limb development | chondrogenesis | membrane potential calcium channel