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Myelin-derived inhibitors limit axon outgrowth and plasticity during development and in the adult mammalian CNS. Nogo66, a functional domain of the myelin-derived inhibitor NogoA, signals through the PirB receptor to inhibit axon outgrowth. The signaling pathway mobilized by Nogo66 engagement of PirB is not well understood. We identify a critical role for the scaffold protein Plenty of SH3s (POSH) in relaying process outgrowth inhibition downstream of Nogo66 and PirB. Blocking the function of POSH, or two POSH-associated proteins, leucine zipper kinase (LZK) and Shroom3, with RNAi in cortical neurons leads to release from myelin and Nogo66 inhibition. We also observed autocrine inhibition of process outgrowth by NogoA, and suppression analysis with the POSH-associated kinase LZK demonstrated that LZK operates downstream of NogoA and PirB in a POSH-dependent manner. In addition, cerebellar granule neurons with an RNAi-mediated knockdown in POSH function were refractory to the inhibitory action of Nogo66, indicating that a POSH-dependent mechanism operates to inhibit axon outgrowth in different types of CNS neurons. These studies delineate an intracellular signaling pathway for process outgrowth inhibition by Nogo66, comprised of NogoA, PirB, POSH, LZK, and Shroom3, and implicate the POSH complex as a potential therapeutic target to enhance axon outgrowth and plasticity in the injured CNS.

POSH is an Intracellular Signal Transducer for the Axon Outgrowth Inhibitor Nogo66