The congenital malformation Split Hand-Foot Malformation (SHFM, or ectrodactyly) is characterized by a medial cleft of hands and feet, and missing central fingers. Five genetically distinct forms are known in humans; the most common (type-1) is linked to deletions of DSS1 and the distalless-related homeogenes DLX5 and DLX6. As Dlx5;D1x6 double-knockout mice show a SHFM-like phenotype, the human orthologs are believed to be the disease genes. SHFM-IV and Ectrodactyly-Ectodermal dysplasia-Cleft lip (EEC) are caused by mutations in p63, an ectoderm-specific p53-related transcription factor. The similarity in the limb phenotype of different forms of SHFM may underlie the existence of a regulatory cascade involving the disease genes. Here, we show that p63 and Dlx proteins colocalize in the nuclei of the apical ectodermal ridge (AER). In homozygous p63- (null) and p63EEC (R279H) mutant limbs, the AER fails to stratify and the expression of four Dlx genes is strongly reduced; interestingly, the p63+/EEC and p63+/- hindlimbs, which develop normally and have a normally stratified AER, show reduced Dlx gene expression. The p63+/EEC mutation combined with an incomplete loss of Dlx5 and Dlx6 alleles leads to severe limb phenotypes, which are not observed in mice with either mutation alone. In vitro, Î”Np63Î± induces transcription from the D1x5 and D1x6 promoters, an activity abolished by EEC and SHFM-IV mutations, but not by Ankyloblepharon-Ectodermal defects-Cleft lip/palate (AEC) mutations. ChIP analysis shows that p63 is directly associated with the Dlx5 and Dlx6 promoters. Thus, our data strongly implicate p63 and the Dlx5-Dlx6 locus in a pathway relevant in the aetio-pathogenesis of SHFM.
Iacono N.L., M.S. (2008). Regulation of Dlx5 and Dlx6 gene expression by p63 is involved in EEC and SHFM congenital limb defects. DEVELOPMENT, 135(7), 1377-1388.
|Tipologia:||Articolo su rivista|
|Citazione:||Iacono N.L., M.S. (2008). Regulation of Dlx5 and Dlx6 gene expression by p63 is involved in EEC and SHFM congenital limb defects. DEVELOPMENT, 135(7), 1377-1388.|
|IF:||Con Impact Factor ISI|
|Settore Scientifico Disciplinare:||Settore MED/35 - Malattie Cutanee e Veneree|
|Revisione (peer review):||Sì, ma tipo non specificato|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1242/dev.011759|
|Stato di pubblicazione:||Pubblicato|
|Data di pubblicazione:||2008|
|Titolo:||Regulation of Dlx5 and Dlx6 gene expression by p63 is involved in EEC and SHFM congenital limb defects|
|Autori:||Iacono N.L., Mantero S., Chiarelli A., Garcia E., Mills A.A., Morasso M.I., Costanzo A., Levi G., Guerrini L., Merlo G.R.|
|Appare nelle tipologie:||01 - Articolo su rivista|