Article

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.

Download full-text

Full-text

Available from: Yesser Belgacem, Aug 14, 2015
0 Followers
 · 
113 Views
  • Source
    • "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 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Among the many forms of brain plasticity, changes in synaptic strength and changes in synapse number are particularly prominent. However, evidence for neurotransmitter respecification or switching has been accumulating steadily, both in the developing nervous system and in the adult brain, with observations of transmitter addition, loss, or replacement of one transmitter with another. Natural stimuli can drive these changes in transmitter identity, with matching changes in postsynaptic transmitter receptors. Strikingly, they often convert the synapse from excitatory to inhibitory or vice versa, providing a basis for changes in behavior in those cases in which it has been examined. Progress has been made in identifying the factors that induce transmitter switching and in understanding the molecular mechanisms by which it is achieved. There are many intriguing questions to be addressed. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neuron 06/2015; 86(5):1131-1144. DOI:10.1016/j.neuron.2015.05.028 · 15.98 Impact Factor
  • Source
    • "(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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Nervous system development relies on the generation of neurons, their differentiation and establishment of synaptic connections. These events exhibit remarkable plasticity and are regulated by many developmental cues. Here, we review the mechanisms of three classes of these cues: morphogenetic proteins, elec-trical activity, and the environment. We focus on second messenger dynamics and their role as integrators of the action of diverse cues, enabling plasticity in the process of neural development. V C 2014 Wiley Periodicals, Inc. Develop
    Developmental Neurobiology 04/2015; 75(4). DOI:10.1002/dneu.22254 · 4.19 Impact Factor
  • Source
    • "To determine whether misexpression of hKir2.1-mCherry in single neurons suppresses Ca 2+ spikes, we assessed Ca 2+ activity in these mCherry-labeled neurons by confocal imaging of Fluo-4 AM. Although neurons located on both dorsal and ventral surfaces spike in situ in X. laevis, those positioned on the dorsal surface spike at lower frequencies at early stages of development (Belgacem and Borodinsky, 2011; Borodinsky et al., 2004; Gu et al., 1994; Root et al., 2008). We thus imaged the intact ventral spinal cord at stage 23-25 when most classes of neurons exhibit a higher incidence and frequency of Ca 2+ spikes (Borodinsky et al., 2004). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Activity-dependent neurotransmitter switching engages genetic programs regulating transmitter synthesis, but the mechanism by which activity is transduced is unknown. We suppressed activity in single neurons in the embryonic spinal cord to determine whether glutamate-gamma-aminobutyric acid (GABA) switching is cell autonomous. Transmitter respecification did not occur, suggesting that it is homeostatically regulated by the level of activity in surrounding neurons. Graded increase in the number of silenced neurons in cultures led to graded decrease in the number of neurons expressing GABA, supporting non-cell-autonomous transmitter switching. We found that brain-derived neurotrophic factor (BDNF) is expressed in the spinal cord during the period of transmitter respecification and that spike activity causes release of BDNF. Activation of TrkB receptors triggers a signaling cascade involving JNK-mediated activation of cJun that regulates tlx3, a glutamate/GABA selector gene, accounting for calcium-spike BDNF-dependent transmitter switching. Our findings identify a molecular mechanism for activity-dependent respecification of neurotransmitter phenotype in developing spinal neurons.
    Neuron 06/2014; 82(5):1004-1016. DOI:10.1016/j.neuron.2014.04.029 · 15.98 Impact Factor
Show more