Human Connexin 32, a gap junction protein altered in the X-linked form of Charcot-Marie-Tooth disease, is directly regulated by the transcription factor SOX10.
Mutations in SOX10, a transcription modulator crucial in the development of the enteric nervous system (ENS), melanocytes and glial cells, are found in Shah-Waardenburg syndrome (WS4), a neurocristopathy that associates intestinal aganglionosis, pigmentation defects and sensorineural deafness. Expression of MITF and RET, two genes that play important roles during melanocyte and ENS development, respectively, are controlled by SOX10. The observation that some WS4 patients present with myelination defects of the central and peripheral nervous systems correlates with the recent finding that P(0), a major component of the peripheral myelin, is another transcriptional target of SOX10. These phenotypic features suggest that SOX10 could regulate expression of other genes involved in the myelination process as well. Thus, we tested the ability of SOX10 to regulate expression of MBP, PMP22 and Connexin 32, three major proteins of the peripheral myelin. Our study shows that this factor, in synergy with EGR2, strongly activates Cx32 expression in vitro by directly binding to its promoter. In agreement with this finding, SOX10 and EGR2 mutants identified in patients with peripheral myelin defects fail to transactivate the Cx32 promoter. Moreover, we show that a mutation of the Cx32 promoter previously described in a patient with the X-linked form of Charcot-Marie-Tooth (CMTX) disease impairs SOX10 function. In addition to providing new insights into the molecular mechanisms underlying some of the peripheral myelin defects observed in CMTX disease, these results further extend the spectrum of genes that are regulated by SOX10.
Bondurand
N
N
Génétique Moléculaire et Physiopathologie, INSERM U468, et Laboratoire de Biochimie et Génétique Moléculaire, AP-HP, Hôpital Henri Mondor, 94010 Créteil Cedex, France.
Girard
M
M
Pingault
V
V
Lemort
N
N
Dubourg
O
O
Goossens
M
M
D001665:Binding Sites; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D017630:Connexins / Q000235:genetics* / Q000502:physiology; D004268:DNA-Binding Proteins / Q000502:physiology*; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006609:High Mobility Group Proteins / Q000502:physiology*; D006801:Humans; D004676:Myelin Basic Protein / Q000235:genetics; D009185:Myelin Proteins / Q000235:genetics; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055757:SOXE Transcription Factors; D014157:Transcription Factors / Q000502:physiology*; D014960:X Chromosome; D000097002:Gap Junction beta-1 Protein
D017630:Connexins; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D004676:Myelin Basic Protein; D009185:Myelin Proteins; D055757:SOXE Transcription Factors; D014157:Transcription Factors; D000097002:Gap Junction beta-1 Protein; C073687:PMP22 protein, human; C527923:SOX10 protein, human