title: Both Schwann cell and axonal defects cause motor peripheral neuropathy in Ebf2-/- mice.
abstract: Charcot-Marie-Tooth neuropathies are frequent hereditary disorders of the nervous system and most cases remain without a molecular definition. Mutations in transcription factors have been previously associated to various types of this disease. Mice carrying a null mutation in Ebf2 transcription factor present peripheral nerve abnormalities. To get insight into Ebf2 function in peripheral nervous system, here we characterize the peripheral neuropathy affecting these mice. We first show that Ebf2 is largely expressed in peripheral nerve throughout postnatal development, its expression being not only restricted to non-myelin forming Schwann cells, but also involving myelin forming Schwann cells and the perineurium. As a consequence, the onset of myelination is delayed and Schwann cell differentiation markers are downregulated in Ebf2-/- mice. Later in development, myelin pathology appears less severe and characterized by isolated clusters of hypomyelinated fibers. However, we find defects in the nerve architecture, such as abnormalities of the nodal region and shorter internodal length. Furthermore, we demonstrate a significant decrease in axonal calibre, with a lack of large calibre axons, and a severe impairment of motor nerve conduction velocity and amplitude, whereas the sensory nerve parameters are less affected. Interestingly, a clinical case with peripheral motor neuropathy and clinical features similar to Ebf2-/- mice phenotype was associated with a deletion encompassing EBF2 human genomic locus. These findings demonstrate that Ebf2 is a new molecule implicated in peripheral nerve development and a potential candidate gene for peripheral nerve disorders.
authors.affiliation: Department of Experimental Medicine, Section of Human Physiology, University of Genova, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Giacomini
authors.forename: Veronica
authors.initials: V
authors.lastname: La Padula
authors.forename: Angelo
authors.initials: A
authors.lastname: Schenone
authors.forename: Massimo
authors.initials: M
authors.lastname: Leandri
authors.forename: Andrea
authors.initials: A
authors.lastname: Contestabile
authors.forename: Diego
authors.initials: D
authors.lastname: Moruzzo
authors.forename: Laurence
authors.initials: L
authors.lastname: Goutebroze
authors.forename: G Giacomo
authors.initials: GG
authors.lastname: Consalez
authors.forename: Fabio
authors.initials: F
authors.lastname: Benfenati
authors.forename: Anna
authors.initials: A
authors.lastname: Corradi
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology*; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016472:Motor Neuron Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D010523:Peripheral Nervous System Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D012583:Schwann Cells / Q000378:metabolism / Q000473:pathology*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; C489922:Ebf2 protein, mouse