Allele-specific genetic interactions between Mitf and Kit affect melanocyte development.
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.
Wen
Bin
B
Developmental Cell Biology and Disease Program, School of Ophthalmology and Optometry and Zhejiang Eye Hospital, Wenzhou, Zhejiang, China.
Chen
Yu
Y
Li
Huirong
H
Wang
Jing
J
Shen
Jie
J
Ma
Aobo
A
Qu
Jia
J
Bismuth
Keren
K
Debbache
Julien
J
Arnheiter
Heinz
H
Hou
Ling
L
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
D051739:Microphthalmia-Associated Transcription Factor; D019009:Proto-Oncogene Proteins c-kit; D001616:beta-Galactosidase