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Proc Natl Acad Sci U S A 2015 Mar 31;11213:4140-5. doi: 10.1073/pnas.1419690112.
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Inversion of Sonic hedgehog action on its canonical pathway by electrical activity.

Belgacem YH , Borodinsky LN .

Sonic hedgehog (Shh) is a morphogenic protein that operates through the Gli transcription factor-dependent canonical pathway to orchestrate normal development of many tissues. Because aberrant levels of Gli activity lead to a wide spectrum of diseases ranging from neurodevelopmental defects to cancer, understanding the regulatory mechanisms of Shh canonical pathway is paramount. During early stages of spinal cord development, Shh specifies neural progenitors through the canonical signaling. Despite persistence of Shh as spinal cord development progresses, Gli activity is switched off by unknown mechanisms. In this study we find that Shh inverts its action on Gli during development. Strikingly, Shh decreases Gli signaling in the embryonic spinal cord by an electrical activity- and cAMP-dependent protein kinase-mediated pathway. The inhibition of Gli activity by Shh operates at multiple levels. Shh promotes cytosolic over nuclear localization of Gli2, induces Gli2 and Gli3 processing into repressor forms, and activates cAMP-responsive element binding protein that in turn represses gli1 transcription. The regulatory mechanisms identified in this study likely operate with different spatiotemporal resolution and ensure effective down-regulation of the canonical Shh signaling as spinal cord development progresses. The developmentally regulated intercalation of electrical activity in the Shh pathway may represent a paradigm for switching from canonical to noncanonical roles of developmental cues during neuronal differentiation and maturation.

PubMed ID: 25829542
PMC ID: PMC4386408
Article link: Proc Natl Acad Sci U S A
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: creb1 gli1 gli2 gli3 h2bc21 mmut odc1 psmd6 ptch1 sag shh sox2
Antibodies: Creb1 Ab1 Sox2 Ab6 gli2 Ab1 gli2 Ab2
Morpholinos: gli2 MO1 gli3 MO3

Article Images: [+] show captions
References [+] :
Balaskas, Gene regulatory logic for reading the Sonic Hedgehog signaling gradient in the vertebrate neural tube. 2012, Pubmed