{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T19:00:21Z","timestamp":1791140421575,"version":"4.1.0"},"reference-count":80,"publisher":"The Company of Biologists","issue":"7","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2008,4,1]]},"abstract":"<jats:p>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 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, \u0394Np63\u03b1 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.<\/jats:p>","DOI":"10.1242\/dev.011759","type":"journal-article","created":{"date-parts":[[2008,3,7]],"date-time":"2008-03-07T21:40:10Z","timestamp":1204926010000},"page":"1377-1388","source":"Crossref","is-referenced-by-count":100,"title":["Regulation of<i>Dlx5<\/i>and<i>Dlx6<\/i>gene expression by p63 is involved in EEC and SHFM congenital limb defects"],"prefix":"10.1242","volume":"135","author":[{"given":"Nadia","family":"Lo Iacono","sequence":"first","affiliation":[{"name":"Dulbecco Telethon Institute, Molecular Biotechnology Center, University of Torino, Via Nizza 52, Torino, 10126, Italy."},{"name":"Department of Biomolecular Science and Biotechnology, University of Milan, Via Celoria 26, 20133 Milan, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Mantero","sequence":"additional","affiliation":[{"name":"Dulbecco Telethon Institute, Molecular Biotechnology Center, University of Torino, Via Nizza 52, Torino, 10126, Italy."},{"name":"CNR Istituto Tecnologie Biomediche, Segrate Milano, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Chiarelli","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Science and Biotechnology, University of Milan, Via Celoria 26, 20133 Milan, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elvin","family":"Garcia","sequence":"additional","affiliation":[{"name":"Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alea A.","family":"Mills","sequence":"additional","affiliation":[{"name":"Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria I.","family":"Morasso","sequence":"additional","affiliation":[{"name":"Developmental Skin Biology Unit, NIAMS, NIH, Bethesda, MD, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Costanzo","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of Rome, TorVergata, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Levi","sequence":"additional","affiliation":[{"name":"Evolution des Re\u0301gulations Endocriniennes CNRS, UMR5166, Muse\u0301um National d'Histoire Naturelle, Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luisa","family":"Guerrini","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Science and Biotechnology, University of Milan, Via Celoria 26, 20133 Milan, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgio R.","family":"Merlo","sequence":"additional","affiliation":[{"name":"Dulbecco Telethon Institute, Molecular Biotechnology Center, University of Torino, Via Nizza 52, Torino, 10126, Italy."},{"name":"CNR Istituto Tecnologie Biomediche, Segrate Milano, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042621290051800_REF1","doi-asserted-by":"crossref","unstructured":"Acampora, D., Merlo, G., Paleari, L., Zerega, B., Mantero, S.,Barbieri, O., Postiglione, M. 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Delta N-p63\u03b1 functions as both a positive and a negative transcriptional regulator and blocks in vitro differentiation of murine keratinocytes. Oncogene22,3635-3644.","DOI":"10.1038\/sj.onc.1206536"},{"key":"2021042621290051800_REF28","doi-asserted-by":"crossref","unstructured":"Koster, M. I. and Roop, D. R. (2004). p63 and epithelial appendage development. Differentiation72,364-370.","DOI":"10.1111\/j.1432-0436.2004.07208002.x"},{"key":"2021042621290051800_REF29","doi-asserted-by":"crossref","unstructured":"Koster, M. I., Kim, S., Mills, A. A., DeMayo, F. J. and Roop, D. R. (2004). p63 is the molecular switch for initiation of an epithelial stratification program. Genes Dev.18,126-131.","DOI":"10.1101\/gad.1165104"},{"key":"2021042621290051800_REF30","doi-asserted-by":"crossref","unstructured":"Koster, M. I., Dai, D., Marinari, B., Sano, Y., Costanzo, A.,Karin, M. and Roop, D. (2007). p63 induces key target genes required for epidermal morphogenesis. Proc. Natl. Acad. Sci. USA104,3255-3260.","DOI":"10.1073\/pnas.0611376104"},{"key":"2021042621290051800_","doi-asserted-by":"crossref","unstructured":"Koutsodontis, G., Vasilaki, E., Chou, W. C., Papakosta, P. and Kardassis, D. (2005). Physical and functional interactions between members of the tumour suppressor p53 and the Sp families of transcription factors: importance for the regulation of genes involved in cell-cycle arrest and apoptosis. Biochem. J.389,443-455.","DOI":"10.1042\/BJ20041980"},{"key":"2021042621290051800_REF32","doi-asserted-by":"crossref","unstructured":"Lanza, M., Marinari, B., Papoutsaki, M., Giustizieri, M. L.,D'Alessandra, Y., Chimenti, S., Guerrini, L. and Costanzo, A.(2006). Cross-talks in the p53 family: \u0394Np63 is an anti-apoptotic target for \u0394Np73\u03b1 and p53 gain of function mutants. Cell Cycle5,1996-2004.","DOI":"10.4161\/cc.5.17.3188"},{"key":"2021042621290051800_REF33","unstructured":"Laurikkala, J., Mikkola, M. L., James, M., Tummers, M., Mills,A. 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