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: 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
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 123 Issue 4 Pg. 1638-46 (Apr 2013) ISSN: 1558-8238 [Electronic] United States
• PMID: 23549079 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• CACNA1C protein, mouse
• Calcium Channels, L-Type
• Morpholinos
• Zebrafish Proteins
• Calcineurin

Topics

• Animals
• Autistic Disorder
• Branchial Region (embryology, metabolism, pathology)
• Calcineurin (metabolism)
• Calcium Channels, L-Type (genetics, metabolism, physiology)
• Calcium Signaling
• Cell Movement
• Cells, Cultured
• Embryo, Mammalian (metabolism)
• Embryo, Nonmammalian (metabolism)
• Gene Expression
• Gene Knockdown Techniques
• Heart (embryology)
• Humans
• Hyperplasia (embryology, genetics, metabolism)
• Hypertrophy (embryology, genetics, metabolism)
• Long QT Syndrome (genetics)
• Mandible (embryology, metabolism, pathology)
• Mice
• Mice, 129 Strain
• Mice, Inbred C57BL
• Morpholinos (genetics)
• Mutation, Missense
• Neural Crest (metabolism)
• Stem Cells (metabolism, physiology)
• Syndactyly (genetics)
• Zebrafish
• Zebrafish Proteins (genetics, metabolism, physiology)