THE W-SH AND PH MUTATIONS AFFECT THE C-KIT EXPRESSION PROFILE - C-KITMISEXPRESSION IN EMBRYOGENESIS IMPAIRS MELANOGENESIS IN W-SH AND PH MUTANT MICE

The receptor tyrosine kinases (RTKs) c-kit and platelet-derived growth factor receptor alpha chain (PDGFRa) are encoded at the white spottin g (W) and patch (Ph) loci on mouse chromosome 5, While W mutations aff ect melanogenesis, gametogenesis, and hematopoiesis, the Ph mutation a ffects melanogenesis and causes early lethality in homozygotes, W-sash (W-sh) is an expression mutation and blocks c-kit expression in certa in cell types and enhances c-kit expression in others, including at si tes important for early melanogenesis. We have determined the effect o f Ph on c-kit expression during embryogenesis in Ph heterozygotes. Imm unohistochemical analysis revealed enhanced c-kit expression in severa l cell types, including sites important for early melanogenesis. We pr opose that in both W-sh and Ph mutant mice c-kit misexpression affects early melanogenesis and is responsible for the pigment deficiency, Mo reover, we have defined the organization of the RTKs in the W/Ph regio n on chromosome 5 and characterized the W-sh mutation by using pulsed- field gel electrophoresis. Whereas the order of the RTK genes was dete rmined as Pdgfra-c-kit-flk1, analysis of the W-sh mutation revealed th at the c-kit and Pdgfra genes are unlinked in W-sh presumably because of an inversion of a small segment of chromosome 5. The Ph mutation co nsists of a deletion including Pdgfra and the 3' deletion endpoint of Ph lies between Pdgfra and c-kit. Therefore, positive 5' upstream elem ents controlling c-kit expression in mast cells and some other cell ty pes are affected by the W-sh mutation and negative elements are affect ed by both the W-sh and the Ph mutation.