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p63 and FGFR: when development meets proliferation.

Dotto GP - EMBO Mol Med (2012)

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, University of Lausanne, Chemin des Boveresses, Epalinges, Switzerland. Paolo.Dotto@unil.ch

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See related article in EMBO Molecular Medicine http://dx.doi.org/10.1002/emmm.201100199 In a rich and comprehensive piece of work, Ferone et al report in this issue of EMBO Molecular Medicine the first mouse model of the AEC (Ankyloblepharon-Ectodermal defects-Cleft lip/palate, OMIM 106260) syndrome (Ferone et al, )... The AEC syndrome is mostly caused by mutations in the p63 SAM domain and differs from the others in the severity of the skin phenotype, the occurrence of ankyloblepharon (eyelid fusion at birth), and absence of ectrodactyly... Cleft palate is also a feature of the AEC syndrome that is shared with the ectrodactyly, ED and cleft lip/palate syndrome (EEC, OMIM 604292) and limb mammary syndrome (LMS, OMIM 603543), but not with the acro-dermato-ungual-lacrimal-tooth syndrome (ADULT, OMIM 103285) syndrome (Rinne et al, )... To this aim, Ferone et al generated mice with a knock-in missense mutation of the p63 SAM domain (p63), which has been found in AEC patients... To provide mechanistic insights, the authors focused at first on the cleft palate, and found that the palatal shelves of p63+/L514F mutant mice elevated normally at E14.5, but were significantly smaller than the control... They further hypothesized that this reduced size and consequent failure to meet in the midline may be the result of reduced cell proliferation... Indeed, while differentiation of keratinocytes at this and later stage was essentially normal in the mutant mice, their proliferative capability was substantially reduced... Paralleling these observations, they found that the size of the keratinocyte stem cell population is reduced in the mutant mice during development, while the intrinsic self-renewal potential of the stem cells that survive after birth is normal... Importantly, this mutant p63–FGFR connection is not limited to the mouse system, as it was also validated in skin from AEC syndrome patients (Fig 1)... Previous in vitro over-expression studies indicated that AEC mutant p63 can suppress the function of wild-type p63α through a dominant-negative mechanism (Koster et al, )... However, the basis for the selective role of the SAM domain in control of p63-dependent transcription remains elusive, and a conclusion of the present study is that it may be best understood in vivo, possibly by proteomic approaches to identify functionally relevant, associated partners... In fact, other genes of relevance to cleft palate development, like IRF6, were also found to be affected in mice with the p63-SAM mutation, even if to a lesser extent than FGFRs... Even for the cleft palate, the authors infer, but do not prove, the existence of a causal link between this abnormality and the keratinocyte hypo-proliferation that they have observed... Interestingly, the recent findings point to a number of p63 missense mutations including one in the SAM domain (Stransky et al, )... Given the connection between this region of p63 and FGFR expression and function established by the Ferone's work, it is tempting to speculate that a similar connection may apply to keratinocyte-tumour development.

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Impact of p63-SAM mutations on palate developmentΔNp63α functions as a positive determinant of FGFR2 and FGFR3 expression. Mutations found in AEC syndrome are sufficient to suppress, in a heterozygous state, FGFR2 and FGFR3 expression. This causes an impairment of proliferation in embryonic ectodermal cells.p63 is interconnected with several pathways that are required for one or more steps of secondary palate development as recently reviewed (Dixon et al, 2011).
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fig01: Impact of p63-SAM mutations on palate developmentΔNp63α functions as a positive determinant of FGFR2 and FGFR3 expression. Mutations found in AEC syndrome are sufficient to suppress, in a heterozygous state, FGFR2 and FGFR3 expression. This causes an impairment of proliferation in embryonic ectodermal cells.p63 is interconnected with several pathways that are required for one or more steps of secondary palate development as recently reviewed (Dixon et al, 2011).

Mentions: Cleft palate is a relatively common developmental abnormality that can be caused by mutations of a number of genes besides p63 (Dixon et al, 2011). Notable among these are molecules involved in FGF signalling, specifically the fibroblast growth factor receptors (FGFR) 2 or 3 and FGF8 (Dixon et al, 2011). The authors noticed that the reported phenotype of mice lacking the epithelial-specific FGFR2b isoform was remarkably similar to that of their p63 mutant mice, including cleft palate and a strongly hypo-plastic and hypo-proliferative skin (Rice et al, 2004). In a carefully orchestrated series of studies, they established that the FGFR2b gene is a direct p63 target gene and that the p63 gene mutation that they are studying is selectively affecting expression of this gene and of the related FGFR3b gene. A demonstration of the functional importance of the p63-FGFR connection was provided by experiments showing that the hypo-proliferative phenotype of keratinocytes with the p63 mutation could be rescued by increased FGFR expression and signalling. Importantly, this mutant p63–FGFR connection is not limited to the mouse system, as it was also validated in skin from AEC syndrome patients (Fig 1).


p63 and FGFR: when development meets proliferation.

Dotto GP - EMBO Mol Med (2012)

Impact of p63-SAM mutations on palate developmentΔNp63α functions as a positive determinant of FGFR2 and FGFR3 expression. Mutations found in AEC syndrome are sufficient to suppress, in a heterozygous state, FGFR2 and FGFR3 expression. This causes an impairment of proliferation in embryonic ectodermal cells.p63 is interconnected with several pathways that are required for one or more steps of secondary palate development as recently reviewed (Dixon et al, 2011).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3376846&req=5

fig01: Impact of p63-SAM mutations on palate developmentΔNp63α functions as a positive determinant of FGFR2 and FGFR3 expression. Mutations found in AEC syndrome are sufficient to suppress, in a heterozygous state, FGFR2 and FGFR3 expression. This causes an impairment of proliferation in embryonic ectodermal cells.p63 is interconnected with several pathways that are required for one or more steps of secondary palate development as recently reviewed (Dixon et al, 2011).
Mentions: Cleft palate is a relatively common developmental abnormality that can be caused by mutations of a number of genes besides p63 (Dixon et al, 2011). Notable among these are molecules involved in FGF signalling, specifically the fibroblast growth factor receptors (FGFR) 2 or 3 and FGF8 (Dixon et al, 2011). The authors noticed that the reported phenotype of mice lacking the epithelial-specific FGFR2b isoform was remarkably similar to that of their p63 mutant mice, including cleft palate and a strongly hypo-plastic and hypo-proliferative skin (Rice et al, 2004). In a carefully orchestrated series of studies, they established that the FGFR2b gene is a direct p63 target gene and that the p63 gene mutation that they are studying is selectively affecting expression of this gene and of the related FGFR3b gene. A demonstration of the functional importance of the p63-FGFR connection was provided by experiments showing that the hypo-proliferative phenotype of keratinocytes with the p63 mutation could be rescued by increased FGFR expression and signalling. Importantly, this mutant p63–FGFR connection is not limited to the mouse system, as it was also validated in skin from AEC syndrome patients (Fig 1).

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, University of Lausanne, Chemin des Boveresses, Epalinges, Switzerland. Paolo.Dotto@unil.ch

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

See related article in EMBO Molecular Medicine http://dx.doi.org/10.1002/emmm.201100199 In a rich and comprehensive piece of work, Ferone et al report in this issue of EMBO Molecular Medicine the first mouse model of the AEC (Ankyloblepharon-Ectodermal defects-Cleft lip/palate, OMIM 106260) syndrome (Ferone et al, )... The AEC syndrome is mostly caused by mutations in the p63 SAM domain and differs from the others in the severity of the skin phenotype, the occurrence of ankyloblepharon (eyelid fusion at birth), and absence of ectrodactyly... Cleft palate is also a feature of the AEC syndrome that is shared with the ectrodactyly, ED and cleft lip/palate syndrome (EEC, OMIM 604292) and limb mammary syndrome (LMS, OMIM 603543), but not with the acro-dermato-ungual-lacrimal-tooth syndrome (ADULT, OMIM 103285) syndrome (Rinne et al, )... To this aim, Ferone et al generated mice with a knock-in missense mutation of the p63 SAM domain (p63), which has been found in AEC patients... To provide mechanistic insights, the authors focused at first on the cleft palate, and found that the palatal shelves of p63+/L514F mutant mice elevated normally at E14.5, but were significantly smaller than the control... They further hypothesized that this reduced size and consequent failure to meet in the midline may be the result of reduced cell proliferation... Indeed, while differentiation of keratinocytes at this and later stage was essentially normal in the mutant mice, their proliferative capability was substantially reduced... Paralleling these observations, they found that the size of the keratinocyte stem cell population is reduced in the mutant mice during development, while the intrinsic self-renewal potential of the stem cells that survive after birth is normal... Importantly, this mutant p63–FGFR connection is not limited to the mouse system, as it was also validated in skin from AEC syndrome patients (Fig 1)... Previous in vitro over-expression studies indicated that AEC mutant p63 can suppress the function of wild-type p63α through a dominant-negative mechanism (Koster et al, )... However, the basis for the selective role of the SAM domain in control of p63-dependent transcription remains elusive, and a conclusion of the present study is that it may be best understood in vivo, possibly by proteomic approaches to identify functionally relevant, associated partners... In fact, other genes of relevance to cleft palate development, like IRF6, were also found to be affected in mice with the p63-SAM mutation, even if to a lesser extent than FGFRs... Even for the cleft palate, the authors infer, but do not prove, the existence of a causal link between this abnormality and the keratinocyte hypo-proliferation that they have observed... Interestingly, the recent findings point to a number of p63 missense mutations including one in the SAM domain (Stransky et al, )... Given the connection between this region of p63 and FGFR expression and function established by the Ferone's work, it is tempting to speculate that a similar connection may apply to keratinocyte-tumour development.

Show MeSH
Related in: MedlinePlus