ArticleHuman molecular genetics2014
DLX5, FGF8 and the Pin1 isomerase control ΔNp63α protein stability during limb development: a regulatory loop at the basis of the SHFM and EEC congenital malformations.
Article in Human molecular genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 40 citations in OpenAlex.
- Safety considerations for cereblon-recruiting targeted protein degraders.Nature reviews. Drug discovery · 2026Review
- CRISPR activation of DLX5 drives neural progenitors to the GnRH cell fate.Journal of molecular endocrinology · 2026Article
- Identification of novel tumor protein 63 variant associated with split-hand/foot malformation and tooth agenesis.Frontiers in medicine · 2026Article
- Fibroblast growth factor 8: Multifaceted role in development and developmental disorder.Genes & diseases · 2025Review
- A Novel TP63 Missense Mutation in the Sumoylation Motif Causes Isolated Split-Hand/Foot Malformation 4: A Pedigree Report and Literature Review.Molecular genetics & genomic medicine · 2025Review
- Article
- The role of p63 in embryonic external genitalia outgrowth in mice.Development, growth & differentiation · 2023Article
- Identification of a novel heterozygous missense TP63 variant in a Chinese pedigree with split-hand/foot malformation.BMC medical genomics · 2022Article
- The p53 family reaches the final frontier: the variegated regulation of the dark matter of the genome by the p53 family in cancer.RNA biology · 2020Article
- Molecular Mechanisms of the Teratogenic Effects of Thalidomide.Pharmaceuticals (Basel, Switzerland) · 2020Review
- Nonsyndromic Split-Hand/Foot Malformation: Recent Classification.Molecular syndromology · 2020Article
- Pinning Down the Transcription: A Role for Peptidyl-ProlylFrontiers in cell and developmental biology · 2020Review
- p63 is a cereblon substrate involved in thalidomide teratogenicity.Nature chemical biology · 2019Article
- Oncogenic Hijacking of the PIN1 Signaling Network.Frontiers in oncology · 2019Review
- Genetic analysis of a congenital split‑hand/split‑foot malformation 4 pedigree.Molecular medicine reports · 2018Article
- The p53 family orchestrates the regulation of metabolism: physiological regulation and implications for cancer therapy.British journal of cancer · 2017Review
- Article
- ΔNp63/DGCR8-Dependent MicroRNAs Mediate Therapeutic Efficacy of HDAC Inhibitors in Cancer.Cancer cell · 2016Article
- The apical ectodermal ridge of the mouse model of ectrodactyly Dlx5;Dlx6-/- shows altered stratification and cell polarity, which are restored by exogenous Wnt5a ligand.Human molecular genetics · 2016Article
- Mycobacterium tuberculosis Peptidyl-Prolyl Isomerases Also Exhibit Chaperone like Activity In-Vitro and In-Vivo.PloS one · 2016Article
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12 authors at 5 institutions in 2 countries.
Funding
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.
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