title: Myelin is dependent on the Charcot-Marie-Tooth Type 4H disease culprit protein FRABIN/FGD4 in Schwann cells.
abstract: Studying the function and malfunction of genes and proteins associated with inherited forms of peripheral neuropathies has provided multiple clues to our understanding of myelinated nerves in health and disease. Here, we have generated a mouse model for the peripheral neuropathy Charcot-Marie-Tooth disease type 4H by constitutively disrupting the mouse orthologue of the suspected culprit gene FGD4 that encodes the small RhoGTPase Cdc42-guanine nucleotide exchange factor Frabin. Lack of Frabin/Fgd4 causes dysmyelination in mice in early peripheral nerve development, followed by profound myelin abnormalities and demyelination at later stages. At the age of 60 weeks, this was accompanied by electrophysiological deficits. By crossing mice carrying alleles of Frabin/Fgd4 flanked by loxP sequences with animals expressing Cre recombinase in a cell type-specific manner, we show that Schwann cell-autonomous Frabin/Fgd4 function is essential for proper myelination without detectable primary contributions from neurons. Deletion of Frabin/Fgd4 in Schwann cells of fully myelinated nerve fibres revealed that this protein is not only required for correct nerve development but also for accurate myelin maintenance. Moreover, we established that correct activation of Cdc42 is dependent on Frabin/Fgd4 function in healthy peripheral nerves. Genetic disruption of Cdc42 in Schwann cells of adult myelinated nerves resulted in myelin alterations similar to those observed in Frabin/Fgd4-deficient mice, indicating that Cdc42 and the Frabin/Fgd4-Cdc42 axis are critical for myelin homeostasis. In line with known regulatory roles of Cdc42, we found that Frabin/Fgd4 regulates Schwann cell endocytosis, a process that is increasingly recognized as a relevant mechanism in peripheral nerve pathophysiology. Taken together, our results indicate that regulation of Cdc42 by Frabin/Fgd4 in Schwann cells is critical for the structure and function of the peripheral nervous system. In particular, this regulatory link is continuously required in adult fully myelinated nerve fibres. Thus, mechanisms regulated by Frabin/Fgd4-Cdc42 are promising targets that can help to identify additional regulators of myelin development and homeostasis, which may crucially contribute also to malfunctions in different types of peripheral neuropathies.
authors.affiliation: Department of Biology, Institute of Molecular Health Sciences, Cell Biology, Swiss Federal Institute of Technology, ETH Zurich, 8093 Zurich,Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Horn
authors.forename: Reto
authors.initials: R
authors.lastname: Baumann
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Pereira
authors.forename: Páris N M
authors.initials: PN
authors.lastname: Sidiropoulos
authors.forename: Christian
authors.initials: C
authors.lastname: Somandin
authors.forename: Hans
authors.initials: H
authors.lastname: Welzl
authors.forename: Claudia
authors.initials: C
authors.lastname: Stendel
authors.forename: Tessa
authors.initials: T
authors.lastname: Lühmann
authors.forename: Carsten
authors.initials: C
authors.lastname: Wessig
authors.forename: Klaus V
authors.initials: KV
authors.lastname: Toyka
authors.forename: João B
authors.initials: JB
authors.lastname: Relvas
authors.forename: Jan
authors.initials: J
authors.lastname: Senderek
authors.forename: Ueli
authors.initials: U
authors.lastname: Suter
mesh_terms: D000367:Age Factors; D000818:Animals; D002478:Cells, Cultured; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics / Q000473:pathology*; D004195:Disease Models, Animal; D004558:Electric Stimulation; D004705:Endocytosis / Q000187:drug effects / Q000235:genetics; D019054:Evoked Potentials, Motor / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D046529:Microscopy, Electron, Transmission; D009154:Mutation / Q000235:genetics; D018991:Myelin Proteolipid Protein / Q000235:genetics; D009186:Myelin Sheath / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D012583:Schwann Cells / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D012584:Sciatic Nerve / Q000166:cytology / Q000473:pathology / Q000503:physiopathology; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics; D014168:Transferrin / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism
chemical_list: C485165:Fgd4 protein, mouse; D018398:Homeodomain Proteins; D008840:Microfilament Proteins; D018991:Myelin Proteolipid Protein; C047516:Plp1 protein, mouse; D034741:RNA, Small Interfering; D014157:Transcription Factors; D014168:Transferrin; C084059:Hb9 protein, mouse; D020764:cdc42 GTP-Binding Protein