title: Experimental Charcot-Marie-Tooth type 1A: a cDNA microarrays analysis.
abstract: To reveal the spectrum of genes that are modulated in Charcot-Marie-Tooth neuropathy type 1A (CMT1A), which is due to overexpression of the gene coding for the peripheral myelin protein 22 (pmp22), we performed a cDNA microarray experiment with cDNA from sciatic nerves of a rat model of the disease. In homozygous pmp22 overexpressing animals, we found a significant down-regulation of 86 genes, while only 23 known genes were up-regulated, suggesting that the increased dosage of pmp22 induces a general down-regulation of gene expression in peripheral nerve tissue. Classification of the modulated genes into functional categories leads to the identification of some pathways altered by overexpression of pmp22. In particular, a selective down-regulation of the ciliary neurotrophic factor transcript and of genes coding for proteins involved in cell cycle regulation, for cytoskeletal components and for proteins of the extracellular matrix, was observed. Cntf expression was further studied by real-time PCR and ELISA technique in pmp22 transgenic sciatic nerves, human CMT1A sural nerve biopsies, and primary cultures of transgenic Schwann cells. According to the results of cDNA microarray analysis, a down-regulation of cntf, both at the mRNA and protein level, was found in all the conditions tested. These results are relevant to reveal the molecular function of PMP22 and the pathogenic mechanism of CMT1A. In particular, finding a specific reduction of cntf expression in CMT1A Schwann cells suggests that overexpression of pmp22 significantly affects the ability of Schwann cells to offer a trophic support to the axon, which could be a factor, among other, responsible for the development of axonal atrophy in human and experimental CMT1A.
authors.affiliation: Department of Neurosciences, Ophthalmology and Genetics, University of Genova, Italy, via De Toni 5, 16132 Genova, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Vigo
authors.forename: Lucilla
authors.initials: L
authors.lastname: Nobbio
authors.forename: Paul Van
authors.initials: PV
authors.lastname: Hummelen
authors.forename: Michele
authors.initials: M
authors.lastname: Abbruzzese
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Mancardi
authors.forename: Nathalie
authors.initials: N
authors.lastname: Verpoorten
authors.forename: Kristien
authors.initials: K
authors.lastname: Verhoeven
authors.forename: Michael W
authors.initials: MW
authors.lastname: Sereda
authors.forename: Klaus-Armin
authors.initials: KA
authors.lastname: Nave
authors.forename: Vincent
authors.initials: V
authors.lastname: Timmerman
authors.forename: Angelo
authors.initials: A
authors.lastname: Schenone
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002478:Cells, Cultured; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000378:metabolism; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics*; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D009185:Myelin Proteins / Q000096:biosynthesis / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D051381:Rats
chemical_list: D018076:DNA, Complementary; D009185:Myelin Proteins; C073687:PMP22 protein, human