title: The Wsh and Ph mutations affect the c-kit expression profile: c-kit misexpression in embryogenesis impairs melanogenesis in Wsh and Ph mutant mice.
abstract: The receptor tyrosine kinases (RTKs) c-kit and platelet-derived growth factor receptor alpha chain (PDG-FRa) are encoded at the white spotting (W) and patch (Ph) loci on mouse chromosome 5. While W mutations affect melanogenesis, gametogenesis, and hematopoiesis, the Ph mutation affects melanogenesis and causes early lethality in homozygotes. W-sash (Wsh) is an expression mutation and blocks c-kit expression in certain cell types and enhances c-kit expression in others, including at sites important for early melanogenesis. We have determined the effect of Ph on c-kit expression during embryogenesis in Ph heterozygotes. Immunohistochemical analysis revealed enhanced c-kit expression in several cell types, including sites important for early melanogenesis. We propose that in both Wsh and Ph mutant mice c-kit misexpression affects early melanogenesis and is responsible for the pigment deficiency. Moreover, we have defined the organization of the RTKs in the W/Ph region on chromosome 5 and characterized the Wsh mutation by using pulsed-field gel electrophoresis. Whereas the order of the RTK genes was determined as Pdgfra-c-kit-flk1, analysis of the Wsh mutation revealed that the c-kit and Pdgfra genes are unlinked in Wsh, presumably because of an inversion of a small segment of chromosome 5. The Ph mutation consists of a deletion including Pdgfra and the 3' deletion endpoint of Ph lies between Pdgfra and c-kit. Therefore, positive 5' upstream elements controlling c-kit expression in mast cells and some other cell types are affected by the Wsh mutation and negative elements are affected by both the Wsh and the Ph mutation.
authors.affiliation: Genetics Program, Memorial Sloan-Kettering Institute, New York, NY, USA.
authors.forename: R
authors.initials: R
authors.lastname: Duttlinger
authors.forename: K
authors.initials: K
authors.lastname: Manova
authors.forename: G
authors.initials: G
authors.lastname: Berrozpe
authors.forename: T Y
authors.initials: TY
authors.lastname: Chu
authors.forename: V
authors.initials: V
authors.lastname: DeLeon
authors.forename: I
authors.initials: I
authors.lastname: Timokhina
authors.forename: R S
authors.initials: RS
authors.lastname: Chaganti
authors.forename: A D
authors.initials: AD
authors.lastname: Zelenetz
authors.forename: R F
authors.initials: RF
authors.lastname: Bachvarova
authors.forename: P
authors.initials: P
authors.lastname: Besmer
mesh_terms: D000818:Animals; D001483:Base Sequence; D002874:Chromosome Mapping; D017931:DNA Primers; D004622:Embryo, Mammalian / Q000502:physiology*; D015870:Gene Expression; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit; D011519:Proto-Oncogenes; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D016184:Receptors, Colony-Stimulating Factor / Q000032:analysis / Q000096:biosynthesis* / Q000235:genetics; D017479:Receptors, Platelet-Derived Growth Factor / Q000096:biosynthesis / Q000235:genetics*; D015183:Restriction Mapping
chemical_list: D017931:DNA Primers; D011518:Proto-Oncogene Proteins; D016184:Receptors, Colony-Stimulating Factor; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor