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First published online March 7, 2008
doi: 10.1242/10.1242/dev.011759

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

Nadia Lo Iacono^1,2, Stefano Mantero^1,3, Anna Chiarelli², Elvin Garcia⁴, Alea A. Mills⁴, Maria I. Morasso⁵, Antonio Costanzo⁶, Giovanni Levi⁷, Luisa Guerrini^2,*, and Giorgio R. Merlo^1,3,*,

¹ Dulbecco Telethon Institute, Molecular Biotechnology Center, University of Torino, Via Nizza 52, Torino, 10126, Italy.
² Department of Biomolecular Science and Biotechnology, University of Milan, Via Celoria 26, 20133 Milan, Italy.
³ CNR Istituto Tecnologie Biomediche, Segrate Milano, Italy.
⁴ Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.
⁵ Developmental Skin Biology Unit, NIAMS, NIH, Bethesda, MD, USA.
⁶ Department of Dermatology, University of Rome, TorVergata, Italy.
⁷ Evolution des Régulations Endocriniennes CNRS, UMR5166, Muséum National d'Histoire Naturelle, Paris, France.

Authors for correspondence (e-mails: luisa.guerrini{at}unimi.it; gmerlo{at}dti.telethon.it)

Accepted 31 January 2008

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, Np63 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.

Key words: Dlx, p63, Ectrodactyly, Limb development, Transcription regulation

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