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Inversion of Sonic hedgehog action on its canonical pathway by electrical activity.

ABSTRACT: 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.

SUBMITTER: Belgacem YH

PROVIDER: S-EPMC4386408 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Inversion of Sonic hedgehog action on its canonical pathway by electrical activity.

Belgacem Yesser H YH Borodinsky Laura N LN

Proceedings of the National Academy of Sciences of the United States of America 20150317 13

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. Desp ...[more]

PMID: 25829542

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Project description:Background:Primary cilia are small non-motile microtubule and cell membrane protrusions expressed on most vertebrate cells, including cortical and hippocampal neurons. These small organelles serve as sensory structures sampling the extracellular environment and reprogramming the transcriptional machinery in response to environmental change. Primary cilia are decorated with a variety of receptor proteins and are necessary for specific signaling cascades such as the Sonic hedgehog (Shh) pathway. Disrupting cilia structure or function results in a spectrum of diseases collectively referred to as ciliopathies. Common to human ciliopathies is cognitive impairment, a symptom also observed in Alzheimer's disease (AD). One hallmark of AD is accumulation of senile plaques composed of neurotoxic Amyloid-? (A?) peptide. The A? peptide is generated by the proteolytic cleavage of the amyloid precursor protein (APP). We set out to determine if A? affects primary cilia structure and the Shh signaling cascade. Methods:We utilized in vitro cell-based assays in combination with fluorescent confocal microscopy to address our study goals. Shh signaling and cilia structure was studied using two different cell lines, mouse NIH3T3 and human HeLa cells. To investigate how A? levels affect Shh signaling and cilia structure in these cells, we utilized naturally secreted A? as well as synthetic A?. Effects on Shh signaling were assessed by luciferase activity while cilia structure was analyzed by fluorescent microscopy. Results:Here, we report that APP localizes to primary cilia and A? treatment results in distorted primary cilia structure. In addition, we demonstrate that A? treatment interrupts canonical Shh signal transduction. Conclusions:Overall, our study illustrates that A? can alter primary cilia structure suggesting that elevated A? levels, like those observed in AD patients, could have similar effects on neuronal primary cilia in the brain. Additionally, our study suggests that A? impairs the Shh signaling pathway. Together our findings shed light on two novel targets for future AD therapeutics.

Dataset Information

Inversion of Sonic hedgehog action on its canonical pathway by electrical activity.

Publications

Inversion of Sonic hedgehog action on its canonical pathway by electrical activity.

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