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GPR17 is an essential regulator for the temporal adaptation of sonic hedgehog signalling in neural tube development.
- Source :
-
Development (Cambridge, England) [Development] 2019 Sep 12; Vol. 146 (17). Date of Electronic Publication: 2019 Sep 12. - Publication Year :
- 2019
-
Abstract
- Dorsal-ventral pattern formation of the neural tube is regulated by temporal and spatial activities of extracellular signalling molecules. Sonic hedgehog (Shh) assigns ventral neural subtypes via activation of the Gli transcription factors. Shh activity in the neural progenitor cells changes dynamically during differentiation, but the mechanisms regulating this dynamicity are not fully understood. Here, we show that temporal change of intracellular cAMP levels confers the temporal Shh signal, and the purinergic G-protein-coupled receptor GPR17 plays an essential role in this regulation. GPR17 is highly expressed in the ventral progenitor regions of the neural tube and acts as a negative regulator of the Shh signal in chick embryos. Although the activation of the GPR17-related signal inhibits ventral identity, perturbation of Gpr17 expression leads to aberrant expansion of ventral neural domains. Notably, perturbation of Gpr17 expression partially inhibits the negative feedback of Gli activity. Moreover, GPR17 increases cAMP activity, suggesting that it exerts its function by inhibiting the processing of Gli3 protein. GPR17 also negatively regulates Shh signalling in neural cells differentiated from mouse embryonic stem cells, suggesting that GPR17 function is conserved among different organisms. Our results demonstrate that GPR17 is a novel negative regulator of Shh signalling in a wide range of cellular contexts.<br />Competing Interests: Competing interestsThe authors declare no competing or financial interests.<br /> (© 2019. Published by The Company of Biologists Ltd.)
- Subjects :
- Animals
Body Patterning physiology
Cell Differentiation genetics
Chick Embryo
Cyclic AMP metabolism
Cyclic AMP-Dependent Protein Kinases metabolism
Embryonic Development physiology
Embryonic Stem Cells metabolism
Gene Expression Regulation, Developmental
Mice
NIH 3T3 Cells
Nerve Tissue Proteins genetics
Neurons metabolism
Receptors, G-Protein-Coupled genetics
Signal Transduction genetics
Transfection
Zinc Finger Protein Gli3 metabolism
Adaptation, Physiological physiology
Hedgehog Proteins metabolism
Nerve Tissue Proteins metabolism
Neural Tube embryology
Receptors, G-Protein-Coupled metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1477-9129
- Volume :
- 146
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- Development (Cambridge, England)
- Publication Type :
- Academic Journal
- Accession number :
- 31444216
- Full Text :
- https://doi.org/10.1242/dev.176784