Calcium influx through L-type Ca sub( v)1.2 Ca super( 2+) 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 Ca super( 2+) channel Ca sub( v)1.2 in nonexcitable cells. How abnormal Ca super( 2+) influx through Ca sub( 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 sub( v)1.2 roles. Here, we show that Ca sub( 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 Ca super( 2+) influx through Ca sub( v)1.2 regulates jaw development. Cranial neural crest migration was unaffected by Ca sub( v)1.2 knockdown, suggesting a role for Ca sub( v)1.2 later in development. Focusing on the mandible, we observed that cellular hypertrophy and hyperplasia depended upon Ca super( 2+) signals through Ca sub( v)1.2, including those that activated the calcineurin signaling pathway. Together, these results provide new insights into the role of voltage-gated Ca super( 2+) channels in nonexcitable cells during development.