title: Genetic deletion of Cadm4 results in myelin abnormalities resembling Charcot-Marie-Tooth neuropathy.
abstract: The interaction between myelinating Schwann cells and the axons they ensheath is mediated by cell adhesion molecules of the Cadm/Necl/SynCAM family. This family consists of four members: Cadm4/Necl4 and Cadm1/Necl2 are found in both glia and axons, whereas Cadm2/Necl3 and Cadm3/Necl1 are expressed by sensory and motor neurons. By generating mice lacking each of the Cadm genes, we now demonstrate that Cadm4 plays a role in the establishment of the myelin unit in the peripheral nervous system. Mice lacking Cadm4 (PGK-Cre/Cadm4(fl/fl)), but not Cadm1, Cadm2, or Cadm3, develop focal hypermyelination characterized by tomacula and myelin outfoldings, which are the hallmark of several Charcot-Marie-Tooth neuropathies. The absence of Cadm4 also resulted in abnormal axon-glial contact and redistribution of ion channels along the axon. These neuropathological features were also found in transgenic mice expressing a dominant-negative mutant of Cadm4 lacking its cytoplasmic domain in myelinating glia Tg(mbp-Cadm4dCT), as well as in mice lacking Cadm4 specifically in Schwann cells (DHH-Cre/Cadm4(fl/fl)). Consistent with these abnormalities, both PGK-Cre/Cadm4(fl/fl) and Tg(mbp-Cadm4dCT) mice exhibit impaired motor function and slower nerve conduction velocity. These findings indicate that Cadm4 regulates the growth of the myelin unit and the organization of the underlying axonal membrane.
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Neev
authors.initials: N
authors.lastname: Golan
authors.forename: Elena
authors.initials: E
authors.lastname: Kartvelishvily
authors.forename: Ivo
authors.initials: I
authors.lastname: Spiegel
authors.forename: Daniela
authors.initials: D
authors.lastname: Salomon
authors.forename: Helena
authors.initials: H
authors.lastname: Sabanay
authors.forename: Katya
authors.initials: K
authors.lastname: Rechav
authors.forename: Anya
authors.initials: A
authors.lastname: Vainshtein
authors.forename: Shahar
authors.initials: S
authors.lastname: Frechter
authors.forename: Galia
authors.initials: G
authors.lastname: Maik-Rachline
authors.forename: Yael
authors.initials: Y
authors.lastname: Eshed-Eisenbach
authors.forename: Takashi
authors.initials: T
authors.lastname: Momoi
authors.forename: Elior
authors.initials: E
authors.lastname: Peles
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000172:deficiency* / Q000235:genetics*; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D017353:Gene Deletion; D007136:Immunoglobulins / Q000172:deficiency* / Q000235:genetics*; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009186:Myelin Sheath / Q000235:genetics / Q000378:metabolism; D009413:Nerve Fibers, Myelinated / Q000378:metabolism* / Q000473:pathology
chemical_list: C498601:CADM4 protein, human; D015815:Cell Adhesion Molecules; D007136:Immunoglobulins