Treasure or artifact: a decade of p63 research speaks for itself

Mikkola, Marja L.; Costanzo, Antonio; Roop, Dennis R.; Koster, Maranke I.

doi:10.1038/cdd.2009.157

Cited by 10 publications

(14 citation statements)

References 20 publications

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“…resulting in the occurrence of normal skin patches (Mikkola et al, 2010). The finding that inactivation of p63 in mice is accompanied by aberrantly increased expression of the Ink4a and Arf tumor suppressors (Su et al, 2009a) supports the idea that p63 is needed to control senescence and apoptosis induction, allowing proper epidermal homeostasis.…”

mentioning

confidence: 84%

p63, a Story of Mice and Men

vanBokhoven

Melino

Candi

et al. 2011

Journal of Investigative Dermatology

155

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The transcription factor p63 is essential for the formation of the epidermis and other stratifying epithelia. This is clearly demonstrated by the severe abnormality of p63-deficient mice and by the development of certain types of ectodermal dysplasias in humans as a result of p63 mutations. Investigation of the in vivo functions of p63 is complicated by the occurrence of 10 different splicing isoforms and by its interaction with the other family members, p53 and p73. In vitro and in vivo models have been used to unravel the functions of p63 and its different isoforms, but the results or their interpretation are often contradictory. This review focuses on what mammalian in vivo models and patient studies have taught us in the last 10 years.

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mentioning

confidence: 84%

p63, a Story of Mice and Men

vanBokhoven

Melino

Candi

et al. 2011

Journal of Investigative Dermatology

155

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“…Given this altered keratin profile and the failure to detect any markers of keratinocyte differentiation, the p63-null phenotype was attributed to a block in lineage commitment of the ectodermal cells to an epidermal fate (Koster et al, 2004;Mills et al, 1999). Recent reports that the mouse model developed by the Bradley laboratory might represent a hypomorphic allele of p63 have sparked additional debate about the shortcomings of the existing genetic models (Mikkola et al, 2010;Talos et al, 2010;Wolff et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

ΔNp63 knockout mice reveal its indispensable role as a master regulator of epithelial development and differentiation

et al. 2012

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SUMMARYThe transcription factor p63 is important in the development of the skin as p63-null mice exhibit striking defects in embryonic epidermal morphogenesis. Understanding the mechanisms that underlie this phenotype is complicated by the existence of multiple p63 isoforms, including TAp63 and DNp63. To investigate the role of DNp63 in epidermal morphogenesis we generated DNp63 knock-in mice in which the DNp63-specific exon is replaced by GFP. Homozygous DNp63 gfp/gfp animals exhibit severe developmental anomalies including truncated forelimbs and the absence of hind limbs, largely phenocopying existing knockouts in which all p63 isoforms are deleted. DNp63-null animals show a poorly developed stratified epidermis comprising isolated clusters of disorganized epithelial cells. Despite the failure to develop a mature stratified epidermis, the patches of DNp63-null keratinocytes are able to stratify and undergo a program of terminal differentiation. However, we observe premature expression of markers associated with terminal differentiation, which is unique to DNp63-null animals and not evident in the skin of mice lacking all p63 isoforms. We posit that the dysregulated and accelerated keratinocyte differentiation phenotype is driven by significant alterations in the expression of key components of the Notch signaling pathway, some of which are direct transcriptional targets of DNp63 as demonstrated by ChIP experiments. The analysis of DNp63 gfp/gfp knockout mice reaffirms the indispensable role of the DN isoform of p63 in epithelial biology and confirms that DNp63-null keratinocytes are capable of committing to an epidermal cell lineage, but are likely to suffer from diminished renewal capacity and an altered differentiation fate.

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“…Mikkola et al2 imply that the most likely explanation for all our observations is that we unknowingly fell victim of numerous mosaic reversion events in which the wild type p63 allele is recreated through spontaneous homologous recombination in individual cells, leading to isolated patches of completely normal wild type skin (see Figure 4 of Mikkola et al2). They further believe that the reason why we were unable to detect reverted alpha (and beta/gamma) p63 transcripts was that we missed the alpha terminus because we analyzed mRNA isolated from whole embryos rather than from isolated skin.…”

Section: Spontaneous Reversion Of the Brdm2 Allele To Restore Wild Tymentioning

confidence: 84%

“…2 of Mikkola et al2 does not show a signal below 43 kDa, it is unclear what antibody and whether sufficient detection sensitivity was used. Surprisingly, Mikkola et al2 mark bands on this blot as non-specific without proving that they are not derived from p63. Non-specific bands can only be declared as such when still present in a global p63KO sample, which is not provided in this blot.…”

Section: Spontaneous Reversion Of the Brdm2 Allele To Restore Wild Tymentioning

confidence: 98%

“…In response to our recent report on the Brdm2 mouse model for p63 function1, Mikkola et al2 raise concerns on three of our statements: 1) They maintain their initial claim that no functional p63 protein of any kind is synthesized in mice homozygous for the Brdm2 allele; 2) they report the occurrence of spontaneous wild-type allelic reversions in these mice, leading to patches of completely normal epidermis, and propose that these normal reverted skin patches are in fact the multilayered epithelia we described; 3) they insist that the Brdm2 allele is phenotypically indistinguishable from a global p63 knockout.…”

mentioning

confidence: 97%

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