Abstract
Ectrodactyly, or Split-Hand/Foot Malformation (SHFM), is a congenital condition characterized by the loss of central rays of hands and feet. The p63 and the DLX5;DLX6 transcription factors, expressed in the embryonic limb buds and ectoderm, are disease genes for these conditions. Mutations of p63 also cause the ectodermal dysplasia–ectrodactyly–cleft lip/palate (EEC) syndrome, comprising SHFM. Ectrodactyly is linked to defects of the apical ectodermal ridge (AER) of the developing limb buds. FGF8 is the key signaling molecule in this process, able to direct proximo-distal growth and patterning of the skeletal primordial of the limbs. In the limb buds of both p63 and Dlx5;Dlx6 murine models of SHFM, the AER is poorly stratified and FGF8 expression is severely reduced. We show here that the FGF8 locus is a downstream target of DLX5 and that FGF8 counteracts Pin1–ΔNp63α interaction. In vivo, lack of Pin1 leads to accumulation of the p63 protein in the embryonic limbs and ectoderm. We show also that ΔNp63α protein stability is negatively regulated by the interaction with the prolyl-isomerase Pin1, via proteasome-mediated degradation; p63 mutant proteins associated with SHFM or EEC syndromes are resistant to Pin1 action. Thus, DLX5, p63, Pin1 and FGF8 participate to the same time- and location-restricted regulatory loop essential for AER stratification, hence for normal patterning and skeletal morphogenesis of the limb buds. These results shed new light on the molecular mechanisms at the basis of the SHFM and EEC limb malformations.
Highlights
The p63 gene codes for a transcription factor related to the p53 and p73 tumor suppressor genes, proposed as a master regulator of epidermal stem cell maintenance and proliferation, able to promote the epithelial stratification program typical of the mammalian skin
As the FGF8 locus appears to be regulated by both p63 and DLX5, we propose a model in which these two Split-Hand/Foot Malformation (SHFM)-causing genes and FGF8 take part in a regulatory loop that opposes Pin1-mediated degradation of p63, permitting stratification and specialization of ectoderm cells into the apical ectodermal ridge (AER), in a time and regionrestricted manner during limb development
The Dlx5;Dlx6 double knockout (DKO) mice represent a valid animal model for SHFM-I, and we set forth to use them to examine whether the loss of Dlx5;Dlx6 may result in altered AER stratification
Summary
The p63 gene codes for a transcription factor related to the p53 and p73 tumor suppressor genes, proposed as a master regulator of epidermal stem cell maintenance and proliferation, able to promote the epithelial stratification program typical of the mammalian skin. Several mutations in the p63 gene have been identified associated with distinct human developmental syndromes, characterized by common features such as limb abnormalities, ectodermal dysplasia, and facial clefts [1,2,3,4] These syndromes are: the ectodermal dysplasia–ectrodactyly–cleft palate (EEC, MIM #129900), the ankyloblepharon–ectodermal. As the FGF8 locus appears to be regulated by both p63 and DLX5, we propose a model in which these two SHFM-causing genes and FGF8 take part in a regulatory loop that opposes Pin1-mediated degradation of p63, permitting stratification and specialization of ectoderm cells into the AER, in a time and regionrestricted manner during limb development. In SHFM type-I, type-III and type-IV, such regulation is impaired leading to reduced AER stratification, limb malformation and skeletal defects
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
