L-type voltage-gated Ca2+ channel CaV1.2 regulates chondrogenesis during limb development
L-type voltage-gated Ca2+ channel CaV1.2 regulates chondrogenesis during limb development
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DOI：
10.1073/pnas.1908981116
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发表时间：
2019-10-22
影响因子：
11.1
通讯作者：
Tabin, Clifford J.
中科院分区：
文献类型：
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作者：
Atsuta, Yuji;Tomizawa, Reiko R.;Tabin, Clifford J.
所有的细胞，包括非兴奋细胞，保持一个离散的跨膜电位（V-跨膜电位），并有能力调节V-跨膜电位和响应自己和邻居的V-跨膜电位的变化。时空变化已被描述在发育中的胚胎组织，在某些情况下，已牵连到影响发育过程。然而，这种变化在V-tagna是如何转化为细胞内的输入，进而调节发育基因的表达和协调模式化组织的形成，仍然是难以捉摸的。在这里，我们的文件，V-肌的肢体间充质开关从超极化去极化状态在早期软骨细胞分化。这种V-V的变化通过L型电压门控Ca 2+通道（VGCC）的Ca（V）1.2，1通过Ca 2+内流增加细胞内Ca 2+信号传导。我们发现，Ca（V）1.2活性是必不可少的软骨形成在发展中的四肢。通过L型VGCC特异性阻断剂或Ca（V）1.2的肢体特异性缺失的药理学抑制，下调软骨细胞分化所必需的基因（包括Sox 9、Col 2a 1和Agc 1）的表达，从而干扰适当的软骨形成。Ca 2+依赖性转录因子NFATc 1是已知的细胞内Ca 2+信号传导的主要转导子，其部分地挽救Sox 9表达。这些数据揭示了Ca（V）1.2在肢体发育中的指导作用，更广泛地扩展了我们对膜电位调节如何用作发育调节机制的理解。
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 Ca(V)1.2, 1 of L-type voltage-gated Ca2+ channels (VGCCs). We find that Ca(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(V)1.2, 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 Ca(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.