title: Calcium influx through L-type CaV1.2 Ca2+ channels regulates mandibular development.
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 CaV1.2 in nonexcitable cells. How abnormal Ca2+ influx through CaV1.2 underlies phenotypes such as the accompanying syndactyly or craniofacial abnormalities in the majority of affected individuals is not readily explained by established CaV1.2 roles. Here, we show that CaV1.2 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 CaV1.2 regulates jaw development. Cranial neural crest migration was unaffected by CaV1.2 knockdown, suggesting a role for CaV1.2 later in development. Focusing on the mandible, we observed that cellular hypertrophy and hyperplasia depended upon Ca2+ signals through CaV1.2, 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.affiliation: Department of Medicine (Cardiology), Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Kapil V
authors.initials: KV
authors.lastname: Ramachandran
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Hennessey
authors.forename: Adam S
authors.initials: AS
authors.lastname: Barnett
authors.forename: Xinhe
authors.initials: X
authors.lastname: Yin
authors.forename: Harriett A
authors.initials: HA
authors.lastname: Stadt
authors.forename: Erika
authors.initials: E
authors.lastname: Foster
authors.forename: Raj A
authors.initials: RA
authors.lastname: Shah
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yazawa
authors.forename: Ricardo E
authors.initials: RE
authors.lastname: Dolmetsch
authors.forename: Margaret L
authors.initials: ML
authors.lastname: Kirby
authors.forename: Geoffrey S
authors.initials: GS
authors.lastname: Pitt
mesh_terms: D000818:Animals; D001321:Autistic Disorder; D001934:Branchial Region / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D019703:Calcineurin / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020013:Calcium Signaling; D002465:Cell Movement; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000378:metabolism; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006321:Heart / Q000196:embryology; D006801:Humans; D006965:Hyperplasia / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D006984:Hypertrophy / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D008133:Long QT Syndrome / Q000235:genetics; D008334:Mandible / Q000196:embryology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D060172:Morpholinos / Q000235:genetics; D020125:Mutation, Missense; D009432:Neural Crest / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism / Q000502:physiology; D013576:Syndactyly / Q000235:genetics; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: C514350:CACNA1C protein, mouse; D020746:Calcium Channels, L-Type; D060172:Morpholinos; D029961:Zebrafish Proteins; D019703:Calcineurin
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