Regulation of Dlx5 and Dlx6 gene expression by p63 is involved in EEC and SHFM congenital limb defects

Lo Iacono, N., Mantero, S., Chiarelli, A., Garcia, E. L., Mills, A. A., Morasso, M. I., Costanzo, A., Levi, G., Guerrini, L., Merlo, G. R. (April 2008) Regulation of Dlx5 and Dlx6 gene expression by p63 is involved in EEC and SHFM congenital limb defects. Development, 135 (7). pp. 1377-1388. ISSN 0950-1991

URL: http://www.ncbi.nlm.nih.gov/pubmed/18326838
DOI: 10.1242/dev.011759

Abstract

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-I) is linked to deletions of DSS1 and the distalless-related homeogenes DLX5 and DLX6. As Dlx5; Dlx6 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 p63(EEC) (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, Delta Np63 alpha induces transcription from the Dlx5 and Dlx6 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.

Item Type: Paper
Uncontrolled Keywords: Dlx p63 ectrodactyly limb development transcription regulation APICAL ECTODERMAL RIDGE CELL-CYCLE ARREST SPLIT FOOT LOCUS TARGET GENES EPIDERMAL MORPHOGENESIS DACTYLAPLASIA MOUSE HOMEOBOX GENES MICE LACKING DNA-SEQUENCE P53
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene expression
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > p63
CSHL Authors:
Communities: CSHL labs > Mills lab
Depositing User: Matt Covey
Date: April 2008
Date Deposited: 25 Feb 2013 20:54
Last Modified: 25 Feb 2013 20:54
Related URLs:
URI: http://repository.cshl.edu/id/eprint/27607

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