title: Allele-specific genetic interactions between Mitf and Kit affect melanocyte development.
abstract: The tyrosine kinase receptor KIT and the transcription factor MITF, each required for melanocyte development, have been shown to interact functionally both in vitro and in vivo. In vitro, KIT signaling leads to MITF phosphorylation, affecting MITF activity and stability. In vivo, the presence of the Mitf (Mi-wh) allele exacerbates the spotting phenotype associated with heterozygosity for Kit mutations. Here, we show that among a series of other Mitf alleles, only the recessive Mitf (mi-bws) mimics the effect of Mitf (Mi-wh) on Kit. Intriguingly, Mitf (mi-bws) is characterized by a splice defect that leads to a reduction of RNAs containing MITF exon 2B which encodes serine-73, a serine phosphorylated upon KIT signaling. Nevertheless, other Mitf alleles that generally affect Mitf RNA levels, or carry a serine-73-to-alanine mutation that specifically reduces exon 2B-containing RNAs, do not show similar interactions with Kit in vivo. We conclude that the recessive Mitf (mi-bws) is a complex allele that can display a semi-dominant effect when present in a Kit-sensitized background. We suggest that human disease variability may equally be due to complex, allele-specific interactions between different genes.
authors.affiliation: Developmental Cell Biology and Disease Program, School of Ophthalmology and Optometry and Zhejiang Eye Hospital, Wenzhou, Zhejiang, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Wen
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.forename: Huirong
authors.initials: H
authors.lastname: Li
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Jie
authors.initials: J
authors.lastname: Shen
authors.forename: Aobo
authors.initials: A
authors.lastname: Ma
authors.forename: Jia
authors.initials: J
authors.lastname: Qu
authors.forename: Keren
authors.initials: K
authors.lastname: Bismuth
authors.forename: Julien
authors.initials: J
authors.lastname: Debbache
authors.forename: Heinz
authors.initials: H
authors.lastname: Arnheiter
authors.forename: Ling
authors.initials: L
authors.lastname: Hou
mesh_terms: D000483:Alleles; D000818:Animals; D047108:Embryonic Development / Q000235:genetics; D006801:Humans; D008544:Melanocytes / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D010858:Pigmentation / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D051739:Microphthalmia-Associated Transcription Factor; D019009:Proto-Oncogene Proteins c-kit; D001616:beta-Galactosidase