title: Rac1 controls Schwann cell myelination through cAMP and NF2/merlin.
abstract: During peripheral nervous system development, Schwann cells (SCs) surrounding single large axons differentiate into myelinating SCs. Previous studies implicate RhoGTPases in SC myelination, but the mechanisms involved in RhoGTPase regulation of SC myelination are unknown. Here, we show that SC myelination is arrested in Rac1 conditional knock-out (Rac1-CKO) mice. Rac1 knock-out abrogated phosphorylation of the effector p21-activated kinase and decreased NF2/merlin phosphorylation. Mutation of NF2/merlin rescued the myelin deficit in Rac1-CKO mice in vivo and the shortened processes in cultured Rac1-CKO SCs in vitro. Mechanistically, cAMP levels and E-cadherin expression were decreased in the absence of Rac1, and both were restored by mutation of NF2/merlin. Reduced cAMP is a cause of the myelin deficiency in Rac1-CKO mice, because elevation of cAMP by rolipram in Rac1-CKO mice in vivo allowed myelin formation. Thus, NF2/merlin and cAMP function downstream of Rac1 signaling in SC myelination, and cAMP levels control Rac1-regulated SC myelination.
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, Cincinnati, Ohio 45229, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Guo
authors.forename: Chandra
authors.initials: C
authors.lastname: Moon
authors.forename: Karen
authors.initials: K
authors.lastname: Niehaus
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
authors.forename: Nancy
authors.initials: N
authors.lastname: Ratner
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D025581:Neurofibromin 2 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D012583:Schwann Cells / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D012584:Sciatic Nerve / Q000378:metabolism / Q000648:ultrastructure; D015398:Signal Transduction / Q000502:physiology; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D015820:Cadherins; D025581:Neurofibromin 2; D000242:Cyclic AMP; D054462:p21-Activated Kinases; D020830:rac1 GTP-Binding Protein