Abstract
Calcium fluxes have been implicated in the specification of the vertebrate embryonic nervous system for some time, but how these fluxes are regulated and how they relate to the rest of the neural induction cascade is unknown. Here we describe Calfacilitin, a transmembrane calcium channel facilitator that increases calcium flux by generating a larger window current and slowing inactivation of the L-type CaV1.2 channel. Calfacilitin binds to this channel and is co-expressed with it in the embryo. Regulation of intracellular calcium by Calfacilitin is required for expression of the neural plate specifiers Geminin and Sox2 and for neural plate formation. Loss-of-function of Calfacilitin can be rescued by ionomycin, which increases intracellular calcium. Our results elucidate the role of calcium fluxes in early neural development and uncover a new factor in the modulation of calcium signalling.
Highlights
Calcium fluxes have been implicated in the specification of the vertebrate embryonic nervous system for some time, but how these fluxes are regulated and how they relate to the rest of the neural induction cascade is unknown
Experiments in a variety of systems have suggested that signals other than BMP inhibition are required for neural induction, including fibroblast growth factor (FGF)[19,20,21,22,23,24], Wnt inhibition[25,26] and calcium/ protein kinase-C signalling[27,28,29,30,31,32,33,34,35,36,37]
In situ hybridization reveals that expression of C3 mRNA starts weakly in the epiblast before gastrulation (Fig. 1a), increases in the future neural plate and thereafter remains expressed throughout the central nervous system (Fig. 1b–f); this pattern of expression is almost identical to the pre-neural marker Sox[347,48]
Summary
Calcium fluxes have been implicated in the specification of the vertebrate embryonic nervous system for some time, but how these fluxes are regulated and how they relate to the rest of the neural induction cascade is unknown. Twelve differentially expressed genes were identified, encoding proteins involved in transcriptional regulation (ERNI17,21, Churchill[43], Sox[3], Otx246), known and putative receptors (TrkC and Asterix45), a putative RNA-binding protein (Obelix45), the retinoid regulator Cyp26A146 and proteins with pro- and anti-apoptotic functions (Dad[1], Fth, HCF44) These genes are expressed at characteristic times following a graft of the organizer, suggesting that the organizer induces a hierarchical succession of states (‘epochs’)[45].
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