Abstract:

Recent publications have begun to elucidate how merlin regulates responses of Schwann cells to nerve injury and how dysregulation of these responses in the absence of merlin likely contributes to schwannoma cell tumorigenesis. When Schwann cells lose contact with axons, merlin becomes phosphorylated leading to increased p75^NTR expression and ultimately to schwannoma cell apoptosis and loss. However, in the absence of functional merlin, Schwann cells become resistant to p75^NTR-mediated apoptosis. Further, p75^NTR signaling elicits a prosurvival response in schwannoma cells, likely contributing to their ability to proliferate and survive in the absence of axons. This pro-survival response may contribute to the relative resistance of vestibular schwannomas cells to chemotherapeutic agents such as kinase inhibitors. Thus, simultaneously targeting p75^NTR and/or NF-kB may sensitize vestibular schwannomas cells to other classes of chemotherapeutic agents. Interestingly, the mechanisms by which vestibular schwannomas cells escape cell death also inform our understanding of normal Schwann cell behavior following nerve injury.