Title: |
Calcium influx through L-type Cav1.2 Ca2+ channels regulates mandibular development. |
Authors: |
Ramachandran, Kapil V., Hennessey, Jessica A., Barnett, Adam S., Xinhe Yin, Stadt, Harriett A., Foster, Erika, Shah, Raj A., Yazawa, Masayuki, Dolmetsch, Ricardo E., Kirby, Margaret L., Pitt, Geoffrey S. |
Source: |
Journal of Clinical Investigation. Apr2013, Vol. 123 Issue 4, p1638-1646. 9p. 6 Color Photographs. |
Subjects: |
GENETIC mutation, GENETIC disorders, ARRHYTHMIA, SYNDACTYLY, CALCIUM channels, LABORATORY zebrafish, LABORATORY mice, CELLULAR signal transduction |
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. [ABSTRACT FROM AUTHOR] |
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Database: |
Health Source: Nursing/Academic Edition |