title: Gpnmb is a melanoblast-expressed, MITF-dependent gene.
abstract: Expression profile analysis clusters Gpnmb with known pigment genes, Tyrp1, Dct, and Si. During development, Gpnmb is expressed in a pattern similar to Mitf, Dct and Si with expression vastly reduced in Mitf mutant animals. Unlike Dct and Si, Gpnmb remains expressed in a discrete population of caudal melanoblasts in Sox10-deficient embryos. To understand the transcriptional regulation of Gpnmb we performed a whole genome annotation of 2,460,048 consensus MITF binding sites, and cross-referenced this with evolutionarily conserved genomic sequences at the GPNMB locus. One conserved element, GPNMB-MCS3, contained two MITF consensus sites, significantly increased luciferase activity in melanocytes and was sufficient to drive expression in melanoblasts in vivo. Deletion of the 5'-most MITF consensus site dramatically reduced enhancer activity indicating a significant role for this site in Gpnmb transcriptional regulation. Future analysis of the Gpnmb locus will provide insight into the transcriptional regulation of melanocytes, and Gpnmb expression can be used as a marker for analyzing melanocyte development and disease progression.
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. sloftus@mail.nih.gov
authors.forename: Stacie K
authors.initials: SK
authors.lastname: Loftus
authors.forename: Anthony
authors.initials: A
authors.lastname: Antonellis
authors.forename: Ivana
authors.initials: I
authors.lastname: Matera
authors.forename: Gabriel
authors.initials: G
authors.lastname: Renaud
authors.forename: Laura L
authors.initials: LL
authors.lastname: Baxter
authors.forename: Duncan
authors.initials: D
authors.lastname: Reid
authors.forename: Tyra G
authors.initials: TG
authors.lastname: Wolfsberg
authors.forename: Yidong
authors.initials: Y
authors.lastname: Chen
authors.forename: Chenwei
authors.initials: C
authors.lastname: Wang
authors.forename: Megana K
authors.initials: MK
authors.lastname: Prasad
authors.forename: Seneca L
authors.initials: SL
authors.lastname: Bessling
authors.forename: Andrew S
authors.initials: AS
authors.lastname: McCallion
authors.forename: Eric D
authors.initials: ED
authors.lastname: Green
authors.forename: Dorothy C
authors.initials: DC
authors.lastname: Bennett
authors.forename: William J
authors.initials: WJ
authors.lastname: Pavan
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000502:physiology; D001483:Base Sequence; D001665:Binding Sites; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000502:physiology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000502:physiology; D004742:Enhancer Elements, Genetic; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000502:physiology; D008156:Luciferases / Q000378:metabolism; D058965:MART-1 Antigen; D008544:Melanocytes / Q000166:cytology / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D009363:Neoplasm Proteins / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D010088:Oxidoreductases / Q000502:physiology; D010858:Pigmentation; D055757:SOXE Transcription Factors / Q000502:physiology; D012689:Sequence Homology, Nucleic Acid; D015533:Transcriptional Activation; D015027:Zebrafish; D058951:gp100 Melanoma Antigen
chemical_list: D000951:Antigens, Neoplasm; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D005136:Eye Proteins; C503042:GPNMB protein, human; C445671:Gpnmb protein, mouse; D058965:MART-1 Antigen; C497234:MITF protein, human; C548667:MLANA protein, human; D008562:Membrane Glycoproteins; D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse; C548668:Mlana protein, mouse; D009363:Neoplasm Proteins; C548637:PMEL protein, human; C548642:Pmel protein, mouse; D055757:SOXE Transcription Factors; C527924:Sox10 protein, mouse; D058951:gp100 Melanoma Antigen; D010088:Oxidoreductases; D008156:Luciferases; C079621:Tyrp1 protein, mouse; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase