Journal
COMMUNICATIONS BIOLOGY
Volume 4, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s42003-021-02718-6
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Funding
- Spanish 'Ministerio de Economia y Competitividad' [SAF2017-84235-R]
- Fundacion Ramon Areces
- Banco de Santander
- Diane Barriere Chair on Synaptic Bioenergetics (ICM Paris Brain Institute)
- 2019 ATIP-Avenir program (Inserm, France)
- 2019 ATIP-Avenir program (CRNS, France)
- ERC [ERC-StG-852873]
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The Hedgehog pathway was identified as a robust controller of GlyT2 expression and transport activity, affecting presynaptic glycine availability. Modulating the activation state of the Hedgehog pathway can influence the levels of GlyT2 expression and transport capability.
The identity of a glycinergic synapse is maintained presynaptically by the activity of a surface glycine transporter, GlyT2, which recaptures glycine back to presynaptic terminals to preserve vesicular glycine content. GlyT2 loss-of-function mutations cause Hyperekplexia, a rare neurological disease in which loss of glycinergic neurotransmission causes generalized stiffness and strong motor alterations. However, the molecular underpinnings controlling GlyT2 activity remain poorly understood. In this work, we identify the Hedgehog pathway as a robust controller of GlyT2 expression and transport activity. Modulating the activation state of the Hedgehog pathway in vitro in rodent primary spinal cord neurons or in vivo in zebrafish embryos induced a selective control in GlyT2 expression, regulating GlyT2 transport activity. Our results indicate that activation of Hedgehog reduces GlyT2 expression by increasing its ubiquitination and degradation. This work describes a new molecular link between the Hedgehog signaling pathway and presynaptic glycine availability. By modulating the activation state of the Hedgehog pathway, de la Rocha-Munoz et al demonstrate that Hedgehog signaling controls the expression and transport activity of the neuronal glycine transporter GlyT2. This work begins to reveal a potential link between the Hedgehog signaling pathway and presynaptic glycine availability.
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