The α/β carboxy-terminal domains of p63 are required for skin and limb development. New insights from the Brdm2 mouse which is not a complete p63 knockout but expresses p63 γ-like proteins

Wolff, Sonja; Talos, Flaminia; Palacios, Gustavo; Beyer, Ulrike; Dobbelstein, Matthias; Moll, Ute M.

doi:10.1038/cdd.2009.25

Cited by 33 publications

(39 citation statements)

References 32 publications

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“…Heterozygous mutations in p63 underlie 7 autosomal-dominant developmental disorders that are characterized by varying combinations of cleft lip, cleft palate, ectodermal dysplasia, and limb abnormalities (7). To date, 2 mouse models of p63 have been reported, one a loss-offunction allele (23) and another recently found to express p63γ isoforms (24,25). Both mouse models exhibit a similar phenotype consisting of severe limb abnormalities, a thin and undifferentiated epidermis, and lack of epidermal derivatives (23,24).…”

Section: Introductionmentioning

confidence: 98%

Cooperation between the transcription factors p63 and IRF6 is essential to prevent cleft palate in mice

Thomason¹,

Zhou²,

Kouwenhoven³

et al. 2010

J. Clin. Invest.

141

191

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Cleft palate is a common congenital disorder that affects up to 1 in 2,500 live human births and results in considerable morbidity to affected individuals and their families. The etiology of cleft palate is complex, with both genetic and environmental factors implicated. Mutations in the transcription factor-encoding genes p63 and interferon regulatory factor 6 (IRF6) have individually been identified as causes of cleft palate; however, a relationship between the key transcription factors p63 and IRF6 has not been determined. Here, we used both mouse models and human primary keratinocytes from patients with cleft palate to demonstrate that IRF6 and p63 interact epistatically during development of the secondary palate. Mice simultaneously carrying a heterozygous deletion of p63 and the Irf6 knockin mutation R84C, which causes cleft palate in humans, displayed ectodermal abnormalities that led to cleft palate. Furthermore, we showed that p63 transactivated IRF6 by binding to an upstream enhancer element; genetic variation within this enhancer element is associated with increased susceptibility to cleft lip. Our findings therefore identify p63 as a key regulatory molecule during palate development and provide a mechanism for the cooperative role of p63 and IRF6 in orofacial development in mice and humans.

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Section: Introductionmentioning

confidence: 98%

Cooperation between the transcription factors p63 and IRF6 is essential to prevent cleft palate in mice

Thomason¹,

Zhou²,

Kouwenhoven³

et al. 2010

J. Clin. Invest.

141

191

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“…In summary, although the overall outcome of the Brdm2 mice analyzed by Wolff et al 4 are not different from those originally described in the original Mills et al…”

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confidence: 80%

“…5 However, this issue remains to be determined. In summary, although the overall outcome of the Brdm2 mice analyzed by Wolff et al 4 are not different from those originally described in the original Mills et al 2 paper, and later confirmed in several publications, the differences are numerous enough to potentially generate a considerable degree of confusion in the field. It is possible that the low p63 mRNA and protein levels were simply missed in the earlier papers, because of technical reasons.…”

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confidence: 82%

“…No additional epithelial differences with respect to the original report were detected in this study and p63 expression was negative by in situ hybridization. The phenotypic differences point to a more general question: are the partial KO mice analyzed by Wolff et al, 4 identical to the Brdm2 mice originally described by Mills et al…”

mentioning

confidence: 99%

“…In this issue of Cell Death Differentiation, Wolff et al 4 performed a set of experiments leading to the conclusion that the Brdm2 mouse model is a partial KO: 4 they detected a truncated p63 transcript, reminiscent, but not identical of the endogenous p63 transcript that encodes the p63g-isoform.…”

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confidence: 99%

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A new p63-deficient mouse model or a fresh look at an old one?

Aberdam

Mantovani

2009

Cell Death Differ

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The p53-related transcription factor p63 gene encodes six isoforms by the use of two promoters -TA and DN -and alternative splicing at the 3 0 -terminus, resulting in a, b, and g variants. Its critical importance in development has been illustrated by the discovery that dominantly inherited mutations in the p63 gene are found in a number of human ectodermal dysplasias with defects in limb and skin development, 1 and by the generation of mouse models lacking p63 by two independent laboratories. Although the strategies for generating these models were different, the phenotypes were very similar: the mice die soon after birth with severe defects in limbs, craniofacial development, and absence of skin. 2,3The phenotypes of the different p63-deficient models -three generated by the Bradley laboratory (p63 Brdm1, p63 Brdm2, and p63 Brdm3) as well as the one generated by the McKeon laboratory -were essentially identical in their more evident manifestations. However, differences in the interpretation of the phenotypes of these models have led to different views regarding the role of p63 in epidermal morphogenesis and tumor susceptibility. This is far from unprecedented, especially as different mouse strains (129Sv/B57BL/6 in Bradley's and B57BL/6/BALB/c in McKeon's) and KO strategies were used. McKeon's model was generated in a 'traditional' way, by deleting exons 6-8, coding for the DNA-binding domain (DBD). On the other hand, Mills et al.2 generated two mouse strains -Brdm1 and Brdm2 -with targeting vectors that used a gap-repair-dependent mechanism to generate ES cells harboring disrupted p63 alleles; the Brdm1 allele is disrupted within exon 6 of the DBD; the Brdm2 allele is disrupted within intron 10, involving the 3 0 -region of the gene: the transcript would be devoid of exons 11-14, which are incorporated in the a-and b-isoforms. The same laboratory has reported another mouse strain -Brdm3 -in which a conventional floxed LoxP insertion hits the DBD coding exons 5-7, encoding the majority of the DBD in the case of the p63 Brdm3 allele. The three Brdm mice are phenotypically identical.In this issue of Cell Death Differentiation, Wolff et al. 4performed a set of experiments leading to the conclusion that the Brdm2 mouse model is a partial KO: 4 they detected a truncated p63 transcript, reminiscent, but not identical of the endogenous p63 transcript that encodes the p63g-isoform.The truncated transcript is entirely consistent with the genomic organization of Brdm2 originally reported by Mills et al.2 Wolff et al. expressed this transcript in transfections and found that the resulting protein was similar to p63g in its ability to transactivate an Mdm2 luciferase reporter. Immunohistochemical analysis using the 4A4 and H137 antibodies showed that p63 is clearly present, although the amount of p63g produced in utero, as determined by western blotting, was barely detectable. Analyses of embryonic sections of McKeon's mice were negative. The g-isoforms lack the SAM domain, a protein-protein interaction module present in ...

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P63 expression plays a role in developmental rate, embryo size, and local morphogenesis

Boughner

Eede

Spring

et al. 2018

Developmental Dynamics

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The α/β carboxy-terminal domains of p63 are required for skin and limb development. New insights from the Brdm2 mouse which is not a complete p63 knockout but expresses p63 γ-like proteins

Cited by 33 publications

References 32 publications

Cooperation between the transcription factors p63 and IRF6 is essential to prevent cleft palate in mice

Cooperation between the transcription factors p63 and IRF6 is essential to prevent cleft palate in mice

A new p63-deficient mouse model or a fresh look at an old one?

P63 expression plays a role in developmental rate, embryo size, and local morphogenesis

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