Pleiotropic and diverse expression of ZFHX1B gene transcripts during mouse and human development supports the various clinical manifestations of the "Mowat-Wilson" syndrome.
ZFHX1B encodes Smad-interacting protein 1, a transcriptional corepressor involved in the transforming growth factors beta (TGFbeta) signaling pathway. ZFHX1B mutations cause a complex developmental phenotype characterized by severe mental retardation (MR) and multiple congenital defects. We compared the distribution of ZFHX1B transcripts during mouse and human embryogenesis as well as in adult mice and humans. This showed that this gene is strongly transcribed at an early stage in the developing peripheral and central nervous systems of both mice and humans, in all neuronal regions of the brains of 25-week human fetuses and adult mice, and at varying levels in numerous nonneural tissues. Northern blot analysis suggested that ZFHX1B undergoes tissue-specific alternative splicing in both species. These results strongly suggest that ZFHX1B determines the transcriptional levels of target genes in various tissues through the combinatorial interactions of its isoforms with different Smad proteins. Thus, as well as causing neural defects, ZFHX1B mutations may also cause other malformations.
Bassez
Guillaume
G
INSERM U468 et Service de Biochimie et Génétique, AP-HP, Hôpital Henri Mondor, Créteil, France.
Camand
Olivier J A
OJ
Cacheux
Valère
V
Kobetz
Alexandra
A
Dastot-Le Moal
Florence
F
Marchant
Dominique
D
Catala
Martin
M
Abitbol
Marc
M
Goossens
Michel
M
D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D019521:Body Patterning / Q000235:genetics; D001921:Brain / Q000002:abnormalities* / Q000378:metabolism* / Q000503:physiopathology; D000013:Congenital Abnormalities / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D019465:Craniofacial Abnormalities / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004622:Embryo, Mammalian / Q000002:abnormalities* / Q000378:metabolism* / Q000503:physiopathology; D005333:Fetus; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D005809:Genes, Regulator / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D009154:Mutation / Q000235:genetics; D009432:Neural Crest / Q000002:abnormalities / Q000378:metabolism / Q000503:physiopathology; D020033:Protein Isoforms / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D051785:Smad Proteins; D015534:Trans-Activators / Q000378:metabolism; D000074165:Zinc Finger E-box Binding Homeobox 2
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D020033:Protein Isoforms; D012097:Repressor Proteins; D051785:Smad Proteins; D015534:Trans-Activators; C492363:ZEB2 protein, human; C120602:ZEB2 protein, mouse; D000074165:Zinc Finger E-box Binding Homeobox 2