title: Sh3tc2 deficiency affects neuregulin-1/ErbB signaling.
abstract: Mutations in SH3TC2 trigger autosomal recessive demyelinating Charcot-Marie-Tooth type 4C (CMT4C) neuropathy. Sh3tc2 is specifically expressed in Schwann cells and is necessary for proper myelination of peripheral axons. In line with the early onset of neuropathy observed in patients with CMT4C, our analyses of the murine model of CMT4C revealed that the myelinating properties of Sh3tc2-deficient Schwann cells are affected at an early stage. This early phenotype is associated with changes in the canonical Nrg1/ErbB pathway involved in control of myelination. We demonstrated that Sh3tc2 interacts with ErbB2 and plays a role in the regulation of ErbB2 intracellular trafficking from the plasma membrane upon Nrg1 activation. Interestingly, both the loss of Sh3tc2 function in mice and the pathological mutations present in CMT4C patients affect ErbB2 internalization, potentially altering its downstream intracellular signaling pathways. Altogether, our results indicate that the molecular mechanism for the axonal size sensing is disturbed in Sh3tc2-deficient myelinating Schwann cells, thus providing a novel insight into the pathophysiology of CMT4C neuropathy.
authors.affiliation: Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Estelle Arnaud
authors.initials: EA
authors.lastname: Gouttenoire
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Lupo
authors.forename: Eduardo
authors.initials: E
authors.lastname: Calpena
authors.forename: Luca
authors.initials: L
authors.lastname: Bartesaghi
authors.forename: Fanny
authors.initials: F
authors.lastname: Schüpfer
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Médard
authors.forename: Fabienne
authors.initials: F
authors.lastname: Maurer
authors.forename: Jacques S
authors.initials: JS
authors.lastname: Beckmann
authors.forename: Jan
authors.initials: J
authors.lastname: Senderek
authors.forename: Francesc
authors.initials: F
authors.lastname: Palau
authors.forename: Carmen
authors.initials: C
authors.lastname: Espinós
authors.forename: Roman
authors.initials: R
authors.lastname: Chrast
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D012583:Schwann Cells / Q000378:metabolism; D012584:Sciatic Nerve / Q000166:cytology / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D020890:Neuregulin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; C552538:Sh3tc2 protein, mouse; C524056:Erbb2 protein, mouse