Radoja N, Guerrini L, Lo Iacono N et al.Homeobox gene Dlx3 is regulated by p63 during ectoderm development: relevance in the pathogenesis of ectodermal dysplasias. Development 134:13-18

University of Milan, Milano, Lombardy, Italy
Development (Impact Factor: 6.46). 02/2007; 134(1):13-8. DOI: 10.1242/dev.02703
Source: PubMed


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.

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    • "Vectors expressing the WT ΔNp63α isoform of, or the disease-linked mutant p63, were previously described (62,63). The DLX5-myc-tagged expression vectors were obtained from OriGene, and previously used (58). "
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    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; 23(14). DOI:10.1093/hmg/ddu096 · 6.39 Impact Factor
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    • "Third, in vitro the Dlx and Msx proteins compete for the same DNA binding sites, form heterodimers via their homeodomain and reciprocally inhibit their transcriptional activities [44], due to the high degree of homology of their homeodomains [37], [43], [45], [46], [47]. However, current literature suggest that Dlx and Msx proteins have distinct functions: Msx1 and Msx2 are known to control cell proliferation and differentiation in a variety of cell types [48], [49], [50], [51], while Dlx genes are implicated in the differentiation of specific cell lineages, such as forebrain interneurons [52], [53], [54], olfactory receptor neurons [55], osteoblasts [35], [56], and the AER and ectoderm [29], [30], [57], [58]. Notably, Dlx and Msx genes have been shown to cooperate only in specific cases [59], [60], [61], but not at all sites where they are co-expressed. "
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    ABSTRACT: The Dlx and Msx homeodomain transcription factors play important roles in the control of limb development. The combined disruption of Msx1 and Msx2, as well as that of Dlx5 and Dlx6, lead to limb patterning defects with anomalies in digit number and shape. Msx1;Msx2 double mutants are characterized by the loss of derivatives of the anterior limb mesoderm which is not observed in either of the simple mutants. Dlx5;Dlx6 double mutants exhibit hindlimb ectrodactyly. While the morphogenetic action of Msx genes seems to involve the BMP molecules, the mode of action of Dlx genes still remains elusive. Here, examining the limb phenotypes of combined Dlx and Msx mutants we reveal a new Dlx-Msx regulatory loop directly involving BMPs. In Msx1;Dlx5;Dlx6 triple mutant mice (TKO), beside the expected ectrodactyly, we also observe the hallmark morphological anomalies of Msx1;Msx2 double mutants suggesting an epistatic role of Dlx5 and Dlx6 over Msx2. In Msx2;Dlx5;Dlx6 TKO mice we only observe an aggravation of the ectrodactyly defect without changes in the number of the individual components of the limb. Using a combination of qPCR, ChIP and bioinformatic analyses, we identify two Dlx/Msx regulatory pathways: 1) in the anterior limb mesoderm a non-cell autonomous Msx-Dlx regulatory loop involves BMP molecules through the AER and 2) in AER cells and, at later stages, in the limb mesoderm the regulation of Msx2 by Dlx5 and Dlx6 occurs also cell autonomously. These data bring new elements to decipher the complex AER-mesoderm dialogue that takes place during limb development and provide clues to understanding the etiology of congenital limb malformations.
    PLoS ONE 01/2013; 8(1):e51700. DOI:10.1371/journal.pone.0051700 · 3.23 Impact Factor
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    • "The hindlimbs (HL) fail to form altogether, while the forelimbs (FL) are severely truncated and lack most of their distal skeletal elements. The altered phenotypes observed in these mutant mice are a direct consequence of altered cellular properties affecting the same tissues and organs as in human EEC, thus these mice have been considered as models of human EEC [21, 50–52]. "
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    ABSTRACT: The p53-related transcription factor p63 is critically important for basic cellular functions during development of the ectoderm and derived structure and tissues, including skin, limb, palate, and hair. On the one side, p63 is required to sustain the proliferation of keratinocyte progenitors, while on the other side it is required for cell stratification, commitment to differentiate, cell adhesion, and epithelial-mesenchymal signaling. Molecules that are components or regulators of the p63 pathway(s) are rapidly being identified, and it comes with no surprise that alterations in the p63 pathway lead to congenital conditions in which the skin and other ectoderm-derived structures are affected. In this paper, we summarize the current knowledge of the molecular and cellular regulations centered on p63, derived from the comprehension of p63-linked human diseases and the corresponding animal models, as well as from cellular models and high-throughput molecular approaches. We point out common themes and features, that allow to speculate on the possible role of p63 downstream events and their potential exploitation in future attempts to correct the congenital defect in preclinical studies.
    BioMed Research International 05/2011; 2011:864904. DOI:10.1155/2011/864904 · 2.71 Impact Factor
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