Abstract
Small GTPases of the Rho and Ras families are important regulators of Schwann cell biology. The Ras-like GTPases RalA and RalB act downstream of Ras in malignant peripheral nerve sheath tumors. However, the physiological role of Ral proteins in Schwann cell development is unknown. Using transgenic mice with ablation of one or both Ral genes, we report that Ral GTPases are crucial for axonal radial sorting. While lack of only one Ral GTPase was dispensable for early peripheral nerve development, ablation of both RalA and RalB resulted in persistent radial sorting defects, associated with hallmarks of deficits in Schwann cell process formation and maintenance. In agreement, ex vivo-cultured Ral-deficient Schwann cells were impaired in process extension and the formation of lamellipodia. Our data indicate further that RalA contributes to Schwann cell process extensions through the exocyst complex, a known effector of Ral GTPases, consistent with an exocyst-mediated function of Ral GTPases in Schwann cells.
Highlights
In peripheral nerves, myelin produced by Schwann cells (SCs) nucleotide-exchange factors (GEFs) and GTPase-activating proenhances conduction velocity by enabling saltatory conduction teins (GAPs; Wennerberg et al, 2005)
Using appropriate transgenic mice, we found that RalA and RalB are functionally redundant in the development of SCs, while simultaneous elimination of both proteins caused severely arrested axonal sorting
SC-specific deletion of RalA in RalB−/− animals causes mild motor impairments in transgenic mice To study the functions of RalA and RalB in developing peripheral nerves, mice deficient for one or both of these GTPases were generated
Summary
Myelin produced by Schwann cells (SCs) nucleotide-exchange factors (GEFs) and GTPase-activating proenhances conduction velocity by enabling saltatory conduction teins (GAPs; Wennerberg et al, 2005). Besides the Rho GTPase of action potentials. SCs are derived from neural crest cells and family, Ras is another small GTPase with a prominent function undergo a series of differentiation steps before forming myelin in diseased SCs. Hyperactive Ras due to mutations of the Ras-. SCs proliferate and expand cellular extensions into bundles of mation of SCs, with active Ras exerting some of its oncogenic unsorted axons to detach individual axons and establish the one- potential through activation of the Ras-like GTPase RalA to-one relationship required for myelination (Webster et al, (Bodempudi et al, 2009). Axons with a diameter of
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