Journal
DEVELOPMENT
Volume 146, Issue 17, Pages -Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dev.176784
Keywords
G-protein-coupled receptor; Chick; Mouse embryonic stem cells; Neural tube; Sonic hedgehog; Temporal adaptation
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Funding
- Japan Society for Promotion of Science [15H06411, 17H03684]
- Ministry of Education, Science and Technology, Japan [19H04781]
- Joint Research Program of the Institute for Genetic Medicine, Hokkaido University
- Takeda Science Foundation
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care
- Uehara Memorial Foundation
- Novartis Foundation (Japan) for the Promotion of Science
- Grants-in-Aid for Scientific Research [17H03684, 19H04781, 15H06411] Funding Source: KAKEN
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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.
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