Cdc42 regulates schwann cell radial sorting and myelin sheath folding through NF2/merlin‐dependent and independent signaling

Abstract

The Rho family GTPase Cdc42 has been implicated in developmental Schwann cell (SC) proliferation, providing sufficient SCs for radial sorting of axons preceding SC differentiation in the peripheral nervous system. We generated Cdc42 conditional knockout (Cdc42-CKO) mice and confirmed aberrant axon sorting in Cdc42-CKO nerves. In adult Cdc42-CKO nerves, blood vessels were enlarged, and mature Remak bundles containing small axons were absent. Abnormal infoldings and outfoldings of myelin sheaths developed in Cdc42-CKO nerves, mimicking pathological features of Charcot-Marie-Tooth (CMT) disease. The NF2/merlin tumor suppressor has been implicated up- and down-stream of Cdc42. In Cdc42-CKO;NF2-del double mutant mice, radial sorting defects seen in Cdc42-CKO nerves were rescued, while changes in myelin sheaths in Cdc42-CKO nerves were not. Phosphorylation of Focal adhesion kinase (FAK) and P-GSK3β, as well as expression of β-catenin were decreased in Cdc42-CKO nerves, and these changes were rescued by NF2/merlin mutation in Cdc42-CKO;NF2-del double mutant mice. Thus, Cdc42 regulates SC radial sorting in vivo through NF2/merlin dependent signaling pathways, while Cdc42 modulation of myelin sheath folding is NF2/merlin independent.

How Schwann Cells Sort Axons

“…For example, the ECM components Laminin 211, Laminin 411, and Collagen XV; their receptors Integrin α6β1, Integrin α7β1 and Dystroglycan, and the Dystroglycan glycosylation enzyme Fukutin are all involved (Berti and others, 2011; Feltri and others, 2002; Occhi and others, 2005; Patton and others, 2008; Pellegatta and others, 2013; Rasi and others, 2010; Saito and others, 2007; Saito and others, 2003; Wallquist and others, 2005; Yang and others, 2005), probably in relationship to the formation of the basal lamina and its control of Schwann cell polarization and signaling. Intracellular signaling molecules that regulate the cytoskeleton are also important, such as ILK, FAK, the RhoGTPases Rac1 and Cdc42, Profilin, Merlin/Nf2 and N-WASp (Benninger and others, 2007; Grove and others, 2007; Guo and others, 2012; Guo and others, 2013b; Jin and others, 2011; Montani and others, 2014; Nodari and others, 2007; Novak and others, 2011; Pereira and others, 2009). These molecules probably regulate actin polymerization to control the dynamics of the cytoplasmic processes that Schwann cells insert into axonal bundles, as these processes are defective or absent in many of these mutants (Benninger and others, 2007; Guo and others, 2012; Guo and others, 2013b; Jin and others, 2011; Montani and others, 2014; Pereira and others, 2009).…”

“…Intracellular signaling molecules that regulate the cytoskeleton are also important, such as ILK, FAK, the RhoGTPases Rac1 and Cdc42, Profilin, Merlin/Nf2 and N-WASp (Benninger and others, 2007; Grove and others, 2007; Guo and others, 2012; Guo and others, 2013b; Jin and others, 2011; Montani and others, 2014; Nodari and others, 2007; Novak and others, 2011; Pereira and others, 2009). These molecules probably regulate actin polymerization to control the dynamics of the cytoplasmic processes that Schwann cells insert into axonal bundles, as these processes are defective or absent in many of these mutants (Benninger and others, 2007; Guo and others, 2012; Guo and others, 2013b; Jin and others, 2011; Montani and others, 2014; Pereira and others, 2009). …”

“…The remodeling of actin cytoskeleton and cell polarity is also regulated by Rho GTPase family members, and several Rho GTPases are required for radial sorting (Benninger and others, 2007; Guo and others, 2013b; Nodari and others, 2007). Rac1 and Cdc42 have been shown to regulate the activation of PKA through Nf2, as the ablation of Nf2 rescues the radial sorting phenotype of both Rac1 and Cdc42 mutant (Guo and others, 2012; Guo and others, 2013b). Recently, it was reported that LKB1/Par4 is phosphorylated by PKA to establish Schwann cell polarity and to promote radial sorting (Shen and others, 2014).…”

Inverted formin 2‐related Charcot‐Marie‐Tooth disease: extension of the mutational spectrum and pathological findings in Schwann cells and axons

“…At least some INF2 mutants change the affinity to CDC42, suggesting that altered CDC42 signaling is relevant for FSGS‐CMT pathophysiology (Boyer et al ., ) . CDC42 has been shown to regulate Schwann cell growth and myelination (Benninger et al ., ; Guo et al ., ) . Examination of nerve biopsies of patients with INF2 mutations has revealed abnormalities of myelinating and non‐myelinating Schwann cells (Boyer et al ., ; Mademan et al ., ; Mathis et al ., ) .…”

Schwann Cell Myelination

“…Arguing against this model, however, maximal N-WASP expression is present in the abaxonal compartment (Jin et al 2011). Other studies suggest that cdc42 may also promote radial sorting, in part, via NF2/merlin (Guo et al 2013). Finally, recent studies suggest that the Rho/ROCK pathway promotes lamellipodia by a separate, parallel pathway involving myosin light-chain kinase (MLCK) and activation of myosin II and by activating the actin-binding protein profilin1; this latter pathway is negatively regulated by ILK (Montani et al 2014).…”