Calcium influx through L-type CaV1.2 Ca2+ channels regulates mandibular development.

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(V)1.2 in nonexcitable cells. How abnormal Ca2+ influx through Ca(V)1.2 underlies phenotypes such as the accompanying syndactyly or craniofacial abnormalities in the majority of affected individuals is not readily explained by established Ca(V)1.2 roles. Here, we show that Ca(V)1.2 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(V)1.2 regulates jaw development. Cranial neural crest migration was unaffected by Ca(V)1.2 knockdown, suggesting a role for Ca(V)1.2 later in development. Focusing on the mandible, we observed that cellular hypertrophy and hyperplasia depended upon Ca2+ signals through Ca(V)1.2, 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.