Spatially restricted hypopigmentation associated with an Ednrbs-modifying locus on mouse chromosome 10.

We have used the varied expressivity of white spotting (hypopigmentation) observed in intrasubspecific crosses of Ednrb(s) mice (Mayer Ednrb(s)/Ednrb(s) and C3HeB/FeJ Ednrb(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. The k10(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 termed k10(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 the k10 critical interval was flanked by D10Mit10 and D10Mit162/D10Mit122 and cosegregates with mast cell growth factor (Mgf). Complementation crosses with a Mgf(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 for k10(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) with Kit(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.