Abstract
Schwann cells are normally quiescent, myelinating glia cells of the peripheral nervous system. Their aberrant proliferation and transformation underlie the development of benign tumors (neurofibromas) as well as deadly malignant peripheral nerve sheath tumors (MPNSTs). We discovered a new driver of MPNSTs, an oncogenic GTPase named RABL6A, that functions in part by inhibiting the RB1 tumor suppressor. RB1 is a key mediator of cellular senescence, a permanent withdrawal from the cell cycle that protects against cell immortalization and transformation. Based on the RABL6A-RB1 link in MPNSTs, we explored the hypothesis that RABL6A promotes Schwann cell proliferation and abrogates their senescence by inhibiting RB1. Using sequentially passaged normal human Schwann cells (NHSCs), we found that the induction of replicative senescence was associated with reduced expression of endogenous RABL6A. Silencing RABL6A in low passage NHSCs caused premature stress-induced senescence, which was largely rescued by co-depletion of RB1. Consistent with those findings, Rabl6-deficient MEFs displayed impaired proliferation and accelerated senescence compared to wildtype MEFs. These results demonstrate that RABL6A is required for maintenance of proper Schwann cell proliferation and imply that aberrantly high RABL6A expression may facilitate malignant transformation.
Highlights
Schwann cells are key components of the peripheral nervous system that surround and insulate nerve axons by producing a myelin sheath [1]
To begin defining RABL6A’s role in Schwann cell senescence, we first examined its expression in primary normal human Schwann cells (NHSCs) at various times during sequential passaging relative to markers of senescence (Figure 1)
Schwann cell derived tumors are most prominent in the context of NF1, where patients develop benign neurofibromas that can transform into painful and deadly malignant peripheral nerve sheath tumors (MPNSTs)
Summary
Schwann cells are key components of the peripheral nervous system that surround and insulate nerve axons by producing a myelin sheath [1]. The Schwann cell lineage gives rise to multiple neoplastic lesions, including neurofibromas (NFs), schwannomas, and malignant peripheral nerve sheath tumors (MPNSTs) [2]. We recently discovered that RABL6A promotes MPNST development in part through its activation of CDKs and inhibition of RB1 [12] This was consistent with our analyses of human tumors revealing RABL6A expression is low in benign NFs and increases through the stepwise transformation process from NFs to ANNUBPs to MPNSTs. Interestingly, while cultured. RABL6A silencing in low-passage NHSCs caused premature stress-induced senescence, which was attenuated by co-depletion of RB1 In agreement with those findings, Rabl6-deficient MEFs displayed impaired proliferation and accelerated senescence compared to wildtype Rabl6+/+ MEFs. Our results highlight that normal levels of RABL6A are required for maintenance of proper Schwann cell biology and proliferation
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