Myelination allows rapid saltatory propagation of action potentials along the axon and is an essential prerequisite for the normal functioning of the nervous system. During peripheral nervous system (PNS) development, myelin-forming Schwann cells (SCs) generate radial lamellipodia to sort and ensheath axons. This process requires controlled cytoskeletal remodeling, and we show that SC lamellipodia formation depends on the function of profilin 1 (Pfn1), an actin-binding protein involved in microfilament polymerization. Pfn1 is inhibited upon phosphorylation by ROCK, a downstream effector of the integrin linked kinase pathway. Thus, a dramatic reduction of radial lamellipodia formation is observed in SCs lacking integrin-linked kinase or treated with the Rho/ROCK activator lysophosphatidic acid. Knocking down Pfn1 expression by lentiviral-mediated shRNA delivery impairs SC lamellipodia formation in vitro, suggesting a direct role for this protein in PNS myelination. Indeed, SC-specific gene ablation of Pfn1 in mice led to profound radial sorting and myelination defects, confirming a central role for this protein in PNS development. Our data identify Pfn1 as a key effector of the integrin linked kinase/Rho/ROCK pathway. This pathway, acting in parallel with integrin β1/LCK/Rac1 and their effectors critically regulates SC lamellipodia formation, radial sorting and myelination during peripheral nervous system maturation.
Author contributions
L.M., T.B.-T., U.S. and J.B.R. were responsible for the project and experimental design. L.M., T.B.-T., J.P.F., J.A.P., N.G.D., R.F., A.B., Y.B., A.F.G., R.T.B., M.C., K.-A.N., R.J.M.F. and D.M. were responsible for experimental work/data analysis. L.M., T.B.-T., J.A.P., U.S. and J.B.R. wrote and edited the manuscript and prepared the figures.
Funding
Work in the J.B.R. lab was funded by the European Regional Development Fund (FEDER), Operational Competitiveness Programme COMPETE, by the Foundation for Science and Technology (FCT) [FCOMP-01-0124-FEDER-007048 (PTDC/BIA-BCM/69841/2006) and FCOMP-01-0124-FEDER-014190 (PTDC/BIA-BCM/112730/2009)] and by the International Foundation for Research in Paraplegia, Zurich. Work in U.S.’s lab was funded by the Swiss National Science Foundation (SNSF) and by the National Center of Competence in Research Neural Plasticity and Repair. L.M. was supported by a Marie-Curie fellowship [AXOGLIA, 236766] and by a Swiss National Science Foundation Marie Heim-Voegtlin fellowship. J.P.F. and A.F.G. were supported by an FCT fellowship [BPD/SFRH/34834/2007, 28640/2006].
