Article

Homeobox gene Dlx3 is regulated by p63 during ectoderm development: relevance in the pathogenesis of ectodermal dysplasias.

Developmental Skin Biology Unit, NIAMS, NIH, Bethesda, MD 20892, USA.
Development (Impact Factor: 6.27). 02/2007; 134(1):13-8. DOI: 10.1242/dev.02703
Source: PubMed

ABSTRACT Ectodermal dysplasias (EDs) are a group of human pathological conditions characterized by anomalies in organs derived from epithelial-mesenchymal interactions during development. Dlx3 and p63 act as part of the transcriptional regulatory pathways relevant in ectoderm derivatives, and autosomal mutations in either of these genes are associated with human EDs. However, the functional relationship between both proteins is unknown. Here, we demonstrate that Dlx3 is a downstream target of p63. Moreover, we show that transcription of Dlx3 is abrogated by mutations in the sterile alpha-motif (SAM) domain of p63 that are associated with ankyloblepharon-ectodermal dysplasia-clefting (AEC) dysplasias, but not by mutations found in ectrodactylyectodermal dysplasia-cleft lip/palate (EEC), Limb-mammary syndrome (LMS) and split hand-foot malformation (SHFM) dysplasias. Our results unravel aspects of the transcriptional cascade of events that contribute to ectoderm development and pathogenesis associated with p63 mutations.

0 Bookmarks
 · 
108 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Dlx3 is essential for osteoblast differentiation and bone formation, and its expression is regulated by bone morphogenetic protein-2 (BMP-2). However, the intimate mechanism of BMP-2 regulation of Dlx3 transcription in osteoblasts is still unknown. Considering the important roles of Smad5 and p38 in osteoblast differentiation, we hypothesized that Smad5 and p38 mediated BMP-2-induced Dlx3 transcription in osteoblasts. We found activation of Smad5 and p38 increased the expression of Dlx3, whereas knocking down Smad5 or inactivation of p38 inhibited BMP-2-induced Dlx3 expression. Both Smad5 and p38 were able to activate Dlx3 promoter activity and p38/Smad5 response elements were located from -698 to -368 in Dlx3 promoter. Two Smad5 binding sites (SBEI and SBEII, TGTCT box) were identified in this region by EMSA and ChIP assay. Deletions and mutagenesis study of the Dlx3 promoter region indicated that the TGTCT boxes are crucial for p38/Smad5-induced Dlx3 promoter activity. At last, we found a cross-talk between p38 and Smad5, and that activation of p38 is necessary for BMP-2-induced Smad5 phosphorylation and nuclear translocation. Overall, we provide a novel insight that BMP-2-induced Dlx3 expression is regulated by p38/Smad5 signaling pathway in osteoblasts. J. Cell. Physiol. © 2013 Wiley Periodicals, Inc.
    Journal of Cellular Physiology 12/2013; 229(7). · 3.87 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Mouse models have greatly helped in elucidating the molecular mechanisms involved in hair formation and regeneration. Recent publications have reviewed the genes involved in mouse hair development based on the phenotype of transgenic, knockout and mutant animal models. While much of this information has been instrumental in determining molecular aspects of human hair development and cycling, mice exhibit a specific pattern of hair morphogenesis and hair distribution throughout the body that cannot be directly correlated to human hair. In this mini-review, we discuss specific aspects of human hair follicle development and present an up-to-date summary of human genetic disorders associated with abnormalities in hair follicle morphogenesis, structure or regeneration.
    Seminars in Cell and Developmental Biology 12/2013; · 6.20 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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 EEC (Ectodermal dysplasia-Ectrodactyly-Cleft lip/palate) syndrome, comprising SHFM. Ectrodactyly is linked to defects of the Apical Ectodermal Ridge (AER) of the developing limb buds. FGF8 is the key signalling 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 to 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.
    Human Molecular Genetics 02/2014; · 6.68 Impact Factor

Full-text

Download
34 Downloads
Available from
Jun 4, 2014