Small Rho GTPases are key regulators of peripheral nerve biology in health and disease

Abstract

A thorough knowledge of the cellular and molecular basis of the structure and function of peripheral nerves is of paramount importance not only for a better understanding of the fascinating biology of the peripheral nervous system but also for providing critical insights into the various diseases affecting peripheral nerves as the firm foundation of potential treatments. Genetic approaches in model organisms, in combination with research on hereditary forms of neuropathies, have contributed significantly to our progress in this field. In this review, we will focus on recent advances using these synergistic approaches that led to the identification of small Rho GTPases and their regulators as crucial functional players in proper development and function of myelinated peripheral nerves, with a particular emphasis on the cell biology of Schwann cells in health and disease.

N-WASP is required for membrane wrapping and myelination by Schwann cells

“…They displayed Schwann cells (Benninger et al, 2007). In addition, Cdc42 may be required for membrane wrapping and transition from promyelinating to myelinating Schwann cells (Krause et al, 2008). In support of this idea, disruption of frabin/FGD4, a GTPase exchange factor that regulates Cdc42 activity (Umikawa et al, 1999), causes demyelinating Charcot-Marie-Tooth (CMT4H) neuropathy (Delague et al, 2007;Stendel et al, 2007).…”

“…3 D). Interestingly, inducible deletion of Cdc42 in Schwann cells (Krause et al, 2008) indicated that it is important for the transition from the promyelinating to the myelinating stage during remyelination, making it likely to regulate this process through N-WASP. Given that Cdc42 is activated by neuregulin (Benninger et al, 2007), N-WASP could provide a direct imperative link between ErbB2/3 receptor signaling and actin rearrangement during myelination.…”

“…In the PNS, Rho/Rho kinase signaling regulates radial sorting (Pereira et al, 2009), suppresses branching, and controls internodal length by promoting the coordinated movement of the myelin sheath around the axon (Melendez-Vasquez et al, 2004). Rac1 and Cdc42 are required for radial axonal sorting; however, they operate by distinct mechanisms (Feltri et al, 2008;Krause et al, 2008). Rac1 is an effector of 1-integrins and is required for Schwann cell process extension (Benninger et al, 2007;Nodari et al, 2007).…”

“…Similarly, Schwann cells associated with axons but failed to ensheath them in co-culture after blocking myosin II activity (Wang et al, 2008). Several studies have also indicated a role for members of the small Rho-GTPase family, Rac1, Cdc42, and RhoA, in PNS myelination (Feltri et al, 2008;Krause et al, 2008;Bauer et al, 2009). These GTPases regulate the assembly of filamentous actin in response to extracellular signaling (Hall, 1998;Etienne-Manneville and Hall, 2002).…”

Low Density Lipoprotein Receptor-related Protein (LRP1) Regulates Rac1 and RhoA Reciprocally to Control Schwann Cell Adhesion and Migration

“…The experiments performed here, which detected changes in total cellular Rho GTPase activity, were not designed to detect subcellular changes in activation of Rac1 or RhoA, which also may be important. In Schwann cells, the ability of Rac1 to regulate lamellipodia formation and process extension is linked to its effects on myelination and axonal sorting (15,46,47).…”