Calcium influx through L-type Ca_V1.2 Ca²⁺ channels regulates mandibular development

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Abstract

The identification of a gain-of-function mutation in CACNA1C as the cause of Timothy Syndrome (TS), a rare disorder characterized by cardiac arrhythmias and syndactyly, highlighted unexpected roles for the L-type voltage-gated Ca²⁺ channel Ca_V1.2 in nonexcitable cells. How abnormal Ca²⁺ influx through Ca_V1.2 underlies phenotypes such as the accompanying syndactyly or craniofacial abnormalities in the majority of affected individuals is not readily explained by established Ca_V1.2 roles. Here, we show that Ca_V1.2 is expressed in the first and second pharyngeal arches within the subset of cells that give rise to jaw primordia. Gain-of-function and loss-of-function studies in mouse, in concert with knockdown/rescue and pharmacological approaches in zebrafish, demonstrated that Ca²⁺ influx through Ca_V1.2 regulates jaw development. Cranial neural crest migration was unaffected by Ca_V1.2 knockdown, suggesting a role for Ca_V1.2 later in development. Focusing on the mandible, we observed that cellular hypertrophy and hyperplasia depended upon Ca²⁺ signals through Ca_V1.2, including those that activated the calcineurin signaling pathway. Together, these results provide new insights into the role of voltage-gated Ca²⁺ channels in nonexcitable cells during development.

Authors

Kapil V. Ramachandran, Jessica A. Hennessey, Adam S. Barnett, Xinhe Yin, Harriett A. Stadt, Erika Foster, Raj A. Shah, Masayuki Yazawa, Ricardo E. Dolmetsch, Margaret L. Kirby, Geoffrey S. Pitt