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 identifyP2RY14 as a critical regulator of SCP self-renewal, SC proliferation and neurofibroma initiation.
The data sets and original figures generated during this study will be available at Synapse Project (https://www.synapse.org/).
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#2018-0103 expiration 01-2022) of Cincinnati Children's Hospital. The protocol was approved by the Committee on the Ethics of Animal Experiments of the Cincinnati Children's Hospital.
© 2022, Patritti Cram et al.
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