title: Identification of Aim-1 as the underwhite mouse mutant and its transcriptional regulation by MITF.
abstract: Animal pigmentation mutants have provided rich models for the identification of genes modulating pathways from melanocyte development to melanoma. One mouse model is the underwhite locus, alleles of which manifest altered pigmentation of both eye and fur, sometimes in an age-dependent fashion. Here we show that the mouse homolog of a recently identified gene whose mutation produces Japanese gold-colored fish, medaka b, maps to the mouse underwhite locus. We identify distinct mutations of this gene, known as Aim-1, in three underwhite mouse alleles and find that structure/function differences correlate with recessive versus dominant inheritance. The human ortholog of AIM-1 was originally identified as a melanocyte-restricted antigen that is recognized by autologous T cells from a patient with melanoma. We also provide evidence that AIM-1 is transcriptionally modulated by MITF, a melanocyte-specific transcription factor essential to pigmentation and a clinical diagnostic marker in human melanoma. Although AIM-1 appears to reside downstream of MITF, chromatin immunoprecipitations do not reveal binding of MITF to a 5'-flanking region containing histone 3 acetylation, indicating that MITF either acts indirectly on AIM-1 or it binds to a remote regulatory sequence. Nevertheless, MITF links AIM-1 expression and the underwhite phenotype to a transcriptional network central to pigmentation in mammals.
authors.affiliation: Division of Pediatric Hematology/Oncology, Children's Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Jinyan
authors.initials: J
authors.lastname: Du
authors.forename: David E
authors.initials: DE
authors.lastname: Fisher
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics*; D003459:Crystallins; D004268:DNA-Binding Proteins / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D008545:Melanoma / Q000378:metabolism; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D051739:Microphthalmia-Associated Transcription Factor; D008969:Molecular Sequence Data; D009687:Nuclear Proteins; D010858:Pigmentation; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D027981:Symporters; D014157:Transcription Factors; D014158:Transcription, Genetic; D044767:Ubiquitin-Protein Ligases
chemical_list: C105445:CRYBG1 protein, human; D002352:Carrier Proteins; D003459:Crystallins; D004268:DNA-Binding Proteins; C497234:MITF protein, human; C486338:Matp protein, mouse; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse; D009687:Nuclear Proteins; D012333:RNA, Messenger; D027981:Symporters; D014157:Transcription Factors; C467728:STUB1 protein, human; D044767:Ubiquitin-Protein Ligases