Spatially Restricted Hypopigmentation Associated with an Ednrb^s -Modifying Locus on Mouse Chromosome 10

Abstract

We have used the varied expressivity of white spotting (hypopigmentation) observed in intrasubspecific crosses ofEdnrb^s mice (MayerEdnrb^s/Ednrb^s and C3HeB/FeJEdnrb^s/Ednrb^s ) to analyze the effects of modifier loci on the patterning of hypopigmentation. We have confirmed that an Ednrb^s modifier locus is present on mouse Chromosome 10. This locus is now termed k10, using the nomenclature established by Dunn in 1920. Thek10^Mayer allele is a recessive modifier that accounts for almost all of the genetic variance of dorsal hypopigmentation. Using intercross analyses we identified a second allele of this locus or a closely linked gene termedk10^C3H . The k10^C3H allele is semidominant and is associated with the penetrance and expressivity of a white forelock phenotype similar to that seen in Waardenburg syndrome. Molecular linkage analysis was used to determine that thek10 critical interval was flanked by D10Mit10 andD10Mit162/D10Mit122 and cosegregates with mast cell growth factor (Mgf). Complementation crosses with aMgf^Sl allele (a 3–5-cM deletion) confirm the semidominant white forelock feature of the k10^C3H allele and the dorsal spotting feature of K10^Mayer allele. MgF was assessed as a candidate gene fork10^Mayer and k10^C3H by sequence and genomic analyses. No molecular differences were observed between the Mayer and C57BL/6J alleles of MgF; however, extensive genomic differences were observed between the C3HeB/FeJ and C57BL/6J alleles. This suggests that alteration of MgF expression in C3H mice may account for the k10^C3H action on white forelock hypopigmentation. Crosses of Ednrb^s withKit^WJ-2 (the receptor for MGF)-deficient mice confirmed the hypothesis that synergistic interaction between the Endothelin and MGF signaling pathways regulates proper neural crest-derived melanocyte development in vivo.