Sonic hedgehog signaling is decoded by calcium spike activity in the developing spinal cord

Department of Physiology and Membrane Biology and Institute for Pediatric Regenerative Medicine, Shriners Hospital for Children and University of California Davis School of Medicine, Sacramento, CA 95817, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 02/2011; 108(11):4482-7. DOI: 10.1073/pnas.1018217108
Source: PubMed

ABSTRACT Evolutionarily conserved hedgehog proteins orchestrate the patterning of embryonic tissues, and dysfunctions in their signaling can lead to tumorigenesis. In vertebrates, Sonic hedgehog (Shh) is essential for nervous system development, but the mechanisms underlying its action remain unclear. Early electrical activity is another developmental cue important for proliferation, migration, and differentiation of neurons. Here we demonstrate the interplay between Shh signaling and Ca(2+) dynamics in the developing spinal cord. Ca(2+) imaging of embryonic spinal cells shows that Shh acutely increases Ca(2+) spike activity through activation of the Shh coreceptor Smoothened (Smo) in neurons. Smo recruits a heterotrimeric GTP-binding protein-dependent pathway and engages both intracellular Ca(2+) stores and Ca(2+) influx. The dynamics of this signaling are manifested in synchronous Ca(2+) spikes and inositol triphosphate transients apparent at the neuronal primary cilium. Interaction of Shh and electrical activity modulates neurotransmitter phenotype expression in spinal neurons. These results indicate that electrical activity and second-messenger signaling mediate Shh action in embryonic spinal neurons.

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Available from: Yesser Belgacem, Aug 14, 2015
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    • "Modified from Walicke and Patterson (1981). a p < 0.05 compared to CM (line 2) b p < 0.05 compared to K + + CM (line 3) 1134 Neuron 86, June 3, 2015 ª2015 Elsevier Inc. Neuron Review (Belgacem and Borodinsky, 2011; Swapna and Borodinsky, 2012 "
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    • "(B) Shh activates Smo, which recruits PLC leading to IP3 transients that correlate with TRPC1 and Ca v -mediated Ca 21 spikes that regulate neurotransmitter specification in developing spinal neurons. Based on the study by Belgacem and Borodinsky (2011). (C) The opposing dorsoventral gradients of BMP and Shh generate a gradient of Ca 21 spike activity that is important for spinal neuron differentiation. "
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