NF1-dependent disruption of the blood-nerve-barrier is improved by blockade of P2RY14.

The blood-nerve-barrier (BNB) that regulates peripheral nerve homeostasis is formed by endoneurial capillaries and perineurial cells surrounding the Schwann cell (SC)-rich endoneurium. Barrier dysfunction is common in human tumorigenesis, including in some nerve tumors. We identify barrier disruption in human deficient neurofibromas, which were characterized by reduced perineurial cell glucose transporter 1 (GLUT1) expression and increased endoneurial fibrin(ogen) deposition. Conditional loss in murine SCs recapitulated these alterations and revealed decreased tight junctions and decreased caveolin-1 () expression in mutant nerves and in tumors, implicating reduced mediated transcytosis in barrier disruption and tumorigenesis. Additionally, elevated receptor tyrosine kinase activity and genetic deletion of increased endoneurial fibrin(ogen), and promoted SC tumor formation. Finally, when SC lacked , genetic loss or pharmacological inhibition of P2RY14 rescued expression and barrier function. Thus, loss of in SC causes dysfunction of the BNB via P2RY14-mediated G-protein coupled receptor (GPCR) signaling.