Oral communication, iL8

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

A novel Sox10 modifier locus identified in a sensitized ENU mutagenesis screen

Melanocytes are specialized, neural crest-derived cells responsible for pigment production in the skin. Disruption in neural crest development can present as altered pigmentation in skin and/or hair and can be associated with debilitating diseases including deafness, blindness, cleft lip, congenital megacolon, and albinism. Collectively, these diseases are referred to as neurocristopathies. Because genetic background is known to affect the severity of neurocristopathies in both humans and mice, we previously established an enhancer screen to identify mutations that increase the phenotypic severity of Sox10 haploinsufficient mice (Sox10LacZ/+), a well-characterized mouse model of human neurocristopathies. This goal of this mutagenesis screen is to identify previously uncharacterized pathways affecting melanocyte development and to generate models relevant for dissecting human disease etiology. From analysis of 600 pedigrees, we identified five dominant modifiers of the Sox10 phenotype (Mos1-5). Mos3 exhibits a unique, Sox10-dependent, semi-dominant phenotype. Mos3/Mos3 homozygotes exhibit embryonic lethality, but Mos3/+ heterozygotes appear indistinguishable from their wild type littermates. On a Sox10LacZ/+ background, heterozygosity for the Mos3 mutation causes white head spotting that is never observed in Sox10LacZ/+ mice. Embryonic analysis shows that Mos3 causes this synergistic reduction in cranial crest-derived melanoblasts by embryonic day 12.5, before a synergistic reduction in trunk melanoblasts is observed. This suggests that compared to other spotting mutants, Mos3 more severely affects the cranial crest and may reveal a novel pathway affecting melanoblast development. Further comparative analysis of phenotypes identified in our screen will contribute to our understanding of genome function and provide additional disease models for human neurocristopathies and melanoma progression.

Advertisement from our sponsor: