Spatially restricted hypopigmentation associated with an Ednrb(s)-modifying locus on mouse chromosome 10

We have used the varied expressivity of white spotting (hypopigmentation) o bserved in intrasubspecific crosses of Ednrb(5) mice (Mayer Ednrb(5)/Ednrb( 5) and C3HeB/Fe) Ednrb(5)/Ednrb(5) to analyze the effects of modifier loci on the patterning of hypopigmentation. We have confirmed that an Ednrb(5) m odifier locus is present on mouse Chromosome 10. This locus is now termed k 10, using the nomenclature established by Dunn in 1920. The k10(Mayer) alle le is a recessive modifier that accounts For almost all of the genetic vari ance of dorsal hypopigmentation. Using intercross analyses we identified a second allele of this locus or a closely linked gene termed k10(C3H). Th, k 10(C3H) allele is semidominant and is associated with the penetrance and ex pressivity of a white forelock phenotype similar to that seen in Waardenbur g syndrome. Molecular linkage analysis was used to determine that the k10 c ritical interval was Ranked by D10Mit10 and D10Mit162/D10Mir122 and cosegre gates with mast cell growth Factor (Mgf). Complementation crosses with a Mp f(SI) allele (a 3-5-cM deletion) confirm the semidominant white forelock fe ature 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 betw een the Mayer and C57BL/6J alleles of MgF; however, extensive genomic diffe rences were observed between the C3HeB/FeJ and C57BL/6J alleles. This sugge sts that alteration of MgF expression in C3H mice may account for the k10(C 3H) action on white forelock hypopigmentation. Crosses of Ednrb(5) with Kit (WJ-2) (the receptor for MGF)-deficient mice confirmed the hypothesis that synergistic interaction between the Endothelin and MCF signaling pathways r egulates proper neural crest-derived melanocyte development in vivo.