Poster presentation, P22

Official XXIst International Pigment Cell Conference website - 21-24 Sept 2011, Bordeaux - France | updated: September 04 2011

Titration of p53 in dark skin mouse mutants causes a spectrum of pigmentary and hematologic phenotypes

During the course of a large-scale mutagenesis project in mice with defects in skin color, we identified missense mutations in Ribosomal protein S19 (Rps19) and Ribosomal protein S20 (Rps20) in two dark skin mutants. Mutations in a third ribosomal protein, Ribosomal protein S6 (Rps6), produced a similar, albeit more severe, dark skin phenotype. Genetic and molecular studies show that the transcription factor p53 is both necessary and sufficient for the pigmentation phenotype, and that skin darkness correlates with the degree of p53 activation in the skin. Using dark skin as an entry point, we found that the ribosomal protein mouse mutants also exhibit a spectrum of hematologic phenotypes that depend upon the underlying ribosomal protein mutation and genetic background. More importantly, like skin color, blood parameters correlate with the degree of p53 activation in bone marrow precursors. Additional work in mice based on mutations of Mdm2, a negative regulator of p53, suggests that stabilization of p53, is indeed, sufficient to induce changes in skin color and bone marrow maturation. Thus, titration of p53 may explain the pleiotropy and spectrum of phenotypic severity observed in human patients with ribosomal protein mutations, and supports an emerging paradigm in which activation of p53 gives rise to a variety of developmental or disease-related phenotypes depending on the amount and tissue-specific context in which activation occurs.

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