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: 9.67). 02/2011; 108(11):4482-7. DOI: 10.1073/pnas.1018217108
Source: PubMed


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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    • "In contrast, Gli3 is supposed to act more likely as an inhibitor of transcription [15]. While the hedgehog protein in Drosophila is a key player in the formation of segment polarity, its best characterized mammalian homologue Sonic hedgehog is involved in the development of the CNS, limbs, skeleton, and internal organs [16] [17] [18] [19] [20]. In the mammalian central nervous system (CNS) SHH is responsible for the patterning of the spinal cord and brain as well as for the proliferation of the cerebellar granule precursor cells [21]. "
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    ABSTRACT: The Sonic Hedgehog (SHH) pathway plays a central role in the developing mammalian CNS. In our study, we aimed to investigate the spatiotemporal SHH pathway expression pattern in human fetal brains. We analyzed 22 normal fetal brains for Shh, Patched, Smoothened, and Gli1-3 expression by immunohistochemistry. In the telencephalon, strongest expression of Shh, Smoothened, and Gli2 was found in the cortical plate (CP) and ventricular zone. Patched was strongly upregulated in the ventricular zone and Gli1 in the CP. In the cerebellum, SHH pathway members were strongly expressed in the external granular layer (EGL). SHH pathway members significantly decreased over time in the ventricular and subventricular zone and in the cerebellar EGL, while increasing levels were found in more superficial telencephalic layers. Our findings show that SHH pathway members are strongly expressed in areas important for proliferation and differentiation and indicate a temporal expression gradient in telencephalic and cerebellar layers probably due to decreased proliferation of progenitor cells and increased differentiation. Our data about the spatiotemporal expression of SHH pathway members in the developing human brain serves as a base for the understanding of both normal and pathological CNS development.
    08/2015; 2015(4):494269. DOI:10.1155/2015/494269
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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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    Neuron 06/2015; 86(5):1131-1144. DOI:10.1016/j.neuron.2015.05.028 · 15.05 Impact Factor
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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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    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
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