Neurofibromin, the Neurofibromatosis Type 1 Ras‐GAP, Is Required for Appropriate P₀ Expression and Myelination

Abstract

The neurofibromatosis type 1 (NF1) gene product, neurofibromin, regulates activation of the Ras intracellular signaling pathway in Schwann cells. Schwann cells purified from mouse embryos with null mutations in the Nf1 gene increase expression of the major myelin glycoprotein P0. v-Ras expression in cultured Schwann cells partially mimics loss of Nf1, suggesting a role for Ras in upregulation of P0 expression in Nf1-deficient cells. We tested whether loss of Nf1 alters the ability of Schwann cells to form myelin. No significant changes in myelin formation resulted when Nf1-deficient or v-Ras-expressing Schwann cells were cultured with normal neurons. Yet, in organotypic cultures of neurons, Schwann cells, and fibroblasts without neurofibromin, myelination was dramatically reduced. We suggest that Nf1-dependent signaling cascades in neurons and/or fibroblasts, as well as Schwann cells, are required for normal myelination.

Magnetization transfer ratio and volumetric analysis of the brain in macrocephalic patients with neurofibromatosis type 1

“…Another possible mechanism for increased brain volume in NF1 patients might be a lack of axonal elimination due to a defective mechanism of apoptosis [30]. Indeed, activation of Ras proteins, which protect some cells from apoptosis, is regulated by neurofibromin [33,34]. If apoptotic axonal elimination occurs in humans as it does in rhesus monkeys, neurofibromin might be responsible for megencephaly in NF1 patients by regulating the Ras pathway [35].…”

Neuroimaging of phakomatoses: overview and advances

“…(4) Normal myelination by Schwann cells [6]. In addition, the gene for oligodendrocyte myelin glycoprotein, a major myelin protein, is embedded within intron 27b of the NF1 gene [7].…”

NF1 loss disrupts Schwann cell–axonal interactions: a novel role for semaphorin 4F

“…Importantly, the cellular organization seen in this system closely resembles the rat dissociation assay described above (Fig. 1E), and is thought to mimic peripheral nerve structure (Rosenbaum et al 1999). Indeed, upon addition of differentiation medium, robust myelination could be achieved at this stage (data not shown).…”