P2RY14 cAMP signaling regulates Schwann cell precursor self-renewal, proliferation, and nerve tumor initiation in a mouse model of neurofibromatosis
Autor: | Jennifer Patritti Cram, Jianqiang Wu, Robert A Coover, Tilat A Rizvi, Katherine E Chaney, Ramya Ravindran, Jose A Cancelas, Robert J Spinner, Nancy Ratner |
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Rok vydání: | 2021 |
Předmět: |
Neurofibroma
Neurofibromatosis 1 Neurofibromin 1 General Immunology and Microbiology General Neuroscience General Medicine General Biochemistry Genetics and Molecular Biology Disease Models Animal Mice Cell Transformation Neoplastic Receptors Purinergic P2Y Cyclic AMP Animals Schwann Cells Cell Self Renewal |
Zdroj: | eLife. 11 |
ISSN: | 2050-084X |
Popis: | Neurofibromatosis type 1 (NF1) is characterized by nerve tumors called neurofibromas, in which Schwann cells (SCs) show deregulated RAS signaling. NF1 is also implicated in regulation of cAMP. We identified the G-protein-coupled receptor (GPCR) P2ry14 in human neurofibromas, neurofibroma-derived SC precursors (SCPs), mature SCs, and mouse SCPs. Mouse Nf1-/- SCP self-renewal was reduced by genetic or pharmacological inhibition of P2ry14. In a mouse model of NF1, genetic deletion of P2ry14 rescued low cAMP signaling, increased mouse survival, delayed neurofibroma initiation, and improved SC Remak bundles. P2ry14 signals via Gi to increase intracellular cAMP, implicating P2ry14 as a key upstream regulator of cAMP. We found that elevation of cAMP by either blocking the degradation of cAMP or by using a P2ry14 inhibitor diminished NF1-/- SCP self-renewal in vitro and neurofibroma SC proliferation in in vivo. These studies identify P2ry14 as a critical regulator of SCP self-renewal, SC proliferation, and neurofibroma initiation. |
Databáze: | OpenAIRE |
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