Merlin status regulates p75NTR expression and apoptotic signaling in Schwann cells following nerve injury

- Acute or gradual nerve injury increases merlin phosphorylation in SCs.
- Loss of functional merlin increases p75NTR expression in SCs.
- The absence of functional merlin blunts SC proliferation following axotomy.
- SCs lacking functional merlin are less sensitive to p75NTR-mediated apoptosis.

After nerve injury, Schwann cells (SCs) dedifferentiate, proliferate, and support axon regrowth. If axons fail to regenerate, denervated SCs eventually undergo apoptosis due, in part, to increased expression of the low-affinity neurotrophin receptor, p75NTR. Merlin is the protein product of the NF2 tumor suppressor gene implicated in SC tumorigenesis. Here we explore the contribution of merlin to SC responses to nerve injury. We find that merlin becomes phosphorylated (growth permissive) in SCs following acute axotomy and following gradual neural degeneration in a deafness model, temporally correlated with increased p75NTR expression. p75NTR levels are elevated in P0SchΔ39-121 transgenic mice that harbor an Nf2 mutation in SCs relative to wild-type mice before axotomy and remain elevated for a longer period of time following injury. Replacement of wild-type, but not phospho-mimetic (S518D), merlin isoforms suppresses p75NTR expression in primary human schwannoma cultures which otherwise lack functional merlin. Despite elevated levels of p75NTR, SC apoptosis following axotomy is blunted in P0SchΔ39-121 mice relative to wild-type mice suggesting that loss of functional merlin contributes to SC resistance to apoptosis. Further, cultured SCs from mice with a tamoxifen-inducible knock-out of Nf2 confirm that SCs lacking functional merlin are less sensitive to p75NTR-mediated cell death. Taken together these results point to a model whereby loss of axonal contact following nerve injury results in merlin phosphorylation leading to increased p75NTR expression. Further, they demonstrate that merlin facilitates p75NTR-mediated apoptosis in SCs helping to explain how neoplastic SCs that lack functional merlin survive long-term in the absence of axonal contact.