Highlights
- •There exists different expression in MITF-M in various coat color mice skin.
- •The specific promoter Tyrp2 could promote the expression of MITF-M.
- •The overexpression of MITF-M increases the melanin content via up-regulating the levels of Tyr, Tyrp1 and Tyrp2.
- •MITF-M regulates melanogenesis signaling pathway and the level of melanosomal protein in mouse melanocytes.
Abstract
Background
Although the impact of the microphthalamia-associated transcription factor (Mitf) signaling pathway on melanocytes progression has been extensively studied, the specific
molecular mechanisms behind MITF-M-enhanced melanin production in melanocytes still
need to be clarified.
Methods
In this study, we analyzed the levels of Mitf-M in skin tissues of different coat mice in order to further reveal the relationship
between Mitf-M and skin pigmentation. To address the function of Mitf-M on melanogenesis, we have used an overexpression system and combined morphological
and biochemical methods to investigate its localization in different coat color mice
and pigmentation-related genes’ expression in mouse melanocytes.
Results
The qRT-PCR assay and Western blotting analysis revealed that Mitf-M mRNA and protein were synthesized in all tested mice skin samples, with the highest
expression level in brown skin, a moderate expression level in grey skin and the lowest
expression level in black skin. Simultaneously, immunofluorescence staining revealed
that MITF-M was mainly expressed in the hair follicle matrix and inner and outer root
sheath in the skin tissues with different coat colors. Furthermore, overexpression
of MITF-M led to increased melanin content and variable pigmentation-related gene
expression.
Conclusion
These results directly demonstrate that MITF-M not only influences melanogenesis,
but also determines the progression of melanosomal protein in mouse melanocytes.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Journal of Dermatological ScienceAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Neue mutationen und koppelungsgruppen bei der hausmaus.Mol. Genet. Genom. 1942; 80: 220-246
- Mutations at the mouse microphthalmia locus are associated with defects in a gene encoding a novel basic-helix-loop-helix-zipper protein.Cell. 1993; 74: 395-404
- MITF: a stream flowing for pigment cells.Pigment Cell Res. 2000; 13: 230-240
- Microphthalmia, a critical factor in melanocyte development, defines a discrete transcription factor family.Genes Dev. 1994; 8: 2770-2780
- The other pigment cell: specification and development of the pigmented epithelium of the vertebrate eye.Pigment Cell Res. 2006; 19: 380-394
- Cloning of MITF, the human homolog of the mouse microphthalmia gene and assignment to chromosome 3p14.1-p12.3.Hum. Mol. Genet. 1994; 3: 553-557
- Alternative promoter use in eye development: the complex role and regulation of the transcription factor MITF.Development. 2008; 135: 1169-1178
- A novel isoform of microphthalmia-associated transcription factor inhibits IL-8 gene expression in human cervical stromal cells.Mol. Endocrinol. 2010; 24: 1512-1528
- MITF: master regulator of melanocyte development and melanoma oncogene.Trends Mol. Med. 2006; 12: 406-414
- Molecular cloning of cDNA encoding a novel microphthalmia-associated transcription factor isoform with a distinct amino-terminus.J. Biochem. 1999; 126: 1043-1051
- Expression of genes for microphthalmia isoforms, Pax3 and MSG1, in human melanomas.Cell. Mol. Biol. (Noisy-le-grand). 1999; 45: 1075-1082
- MITF-M, a ‘melanocyte-specific’ isoform, is expressed in the adult retinal pigment epithelium.Pigment Cell Melanoma Res. 2012; 25: 641-644
- Identification of a novel isoform of microphthalmia-associated transcription factor that is enriched in retinal pigment epithelium.Biochem. Biophys. Res. Commun. 1998; 247: 710-715
- Structural organization of the human microphthalmia-associated transcription factor gene containing four alternative promoters.Biochim. Biophys. Acta. 2000; 1491: 205-219
- Transcription physiology of pigment formation in melanocytes: central role of MITF.Exp. Dermatol. 2010; 19: 617-627
- Molecular network associated with MITF in skin melanoma development and progression.J. Skin Cancer. 2011; 2011: 730170
- Retinal pigmented epithelium determination requires the redundant activities of Pax2 and Pax6.Development. 2003; 130: 2903-2915
- PAX6 regulates melanogenesis in the retinal pigmented epithelium through feed-forward regulatory interactions with MITF.PLoS Genet. 2014; 10: e1004360
- Ser298 of MITF, a mutation site in Waardenburg syndrome type 2, is a phosphorylation site with functional significance.Hum. Mol. Genet. 2000; 9: 125-132
- Microphthalmia transcription factor is a target of the p38 MAPK pathway in response to receptor activator of NF-kappa B ligand signaling.J. Biol. Chem. 2002; 277: 11077-11083
- MAP kinase links the transcription factor Microphthalmia to c-Kit signalling in melanocytes.Nature. 1998; 391: 298-301
- c-Kit triggers dual phosphorylations, which couple activation and degradation of the essential melanocyte factor Mi.Genes Dev. 2000; 14: 301-312
- Regulation of microphthalmia-associated transcription factor MITF protein levels by association with the ubiquitin-conjugating enzyme hUBC9.Exp. Cell Res. 2000; 255: 135-143
- Sumoylation modulates transcriptional activity of MITF in a promoter-specific manner.Pigment Cell Res. 2005; 18: 265-277
- Melanocyte-specific expression of the human tyrosinase promoter: activation by the microphthalmia gene product and role of the initiator.Mol. Cell. Biol. 1994; 14: 7996-8006
- Functional analysis of microphthalmia-associated transcription factor in pigment cell-specific transcription of the human tyrosinase family genes.J. Biol. Chem. 1997; 272: 503-509
- Proteomic analysis of early melanosomes: identification of novel melanosomal proteins.J. Proteome Res. 2003; 2: 69-79
- Melanocyte biology and skin pigmentation.Nature. 2007; 445: 843-850
- DOPA-negative melanocytes in the outer root sheath of human hair follicles express premelanosomal antigens but not a melanosomal antigen or the melanosome-associated glycoproteins tyrosinase, TRP-1, and TRP-2.J. Invest. Dermatol. 1996; 106: 28-35
- Different populations of melanocytes are present in hair follicles and epidermis.Pigment Cell Res. 1996; 9: 304-310
- Hair follicle pigmentation.J. Invest. Dermatol. 2005; 124: 13-21
- Aging, graying and loss of melanocyte stem cells.Stem Cell Rev. 2007; 3: 212-217
- The microphthalmia transcription factor (Mitf) controls expression of the ocular albinism type 1 gene: link between melanin synthesis and melanosome biogenesis.Mol. Cell. Biol. 2004; 24: 6550-6559
- The ocular albinism type 1 (OA1) gene controls melanosome maturation and size.Invest. Ophthalmol. Vis. Sci. 2005; 46: 4358-4364
- The ocular albinism type 1 protein, an intracellular G protein-coupled receptor, regulates melanosome transport in pigment cells.Hum. Mol. Genet. 2008; 17: 3487-3501
- Signaling pathways in melanosome biogenesis and pathology.Int. J. Biochem. Cell Biol. 2010; 42: 1094-1104
- Melanosome-autonomous regulation of size and number: the OA1 receptor sustains PMEL expression.Pigment Cell Melanoma Res. 2014; 27: 565-579
- Ocular albinism type 1 regulates melanogenesis in mouse melanocytes.Int. J. Mol. Sci. 2016; 17
- Identification of Aim-1 as the underwhite mouse mutant and its transcriptional regulation by MITF.J. Biol. Chem. 2002; 277: 402-406
- Promoter polymorphisms in the MATP (SLC45A2) gene are associated with normal human skin color variation.Hum. Mutat. 2007; 28: 710-717
- The relationship between Na(+)/H(+) exchanger expression and tyrosinase activity in human melanocytes.Exp. Cell Res. 2004; 298: 521-534
- Slc45a2 and V-ATPase are regulators of melanosomal pH homeostasis in zebrafish, providing a mechanism for human pigment evolution and disease.Pigment Cell Melanoma Res. 2013; 26: 205-217
- Membrane-associated transporter protein (MATP) regulates melanosomal pH and influences tyrosinase activity.PLoS One. 2015; 10: e0129273
- Oculocutaneous albinism: developing novel antibodies targeting the proteins associated with OCA2 and OCA4.J. Dermatol. Sci. 2015; 77: 21-27
- The color loci of mice?a genetic century.Pigment Cell Res. 2003; 16: 333-344
- Genetic context determines susceptibility to intraocular pressure elevation in a mouse pigmentary glaucoma.BMC Biol. 2006; 4: 20
- Mutations in genes encoding melanosomal proteins cause pigmentary glaucoma in DBA/2J mice.Nat. Genet. 2002; 30: 81-85
- Gpnmb is a melanoblast-expressed, MITF-dependent gene.Pigment Cell Melanoma Res. 2009; 22: 99-110
- Silencing of GPNMB by siRNA inhibits the formation of melanosomes in melanocytes in a MITF-independent fashion.PLoS One. 2012; 7: e42955
- GPNMB affects melanin synthesis in the melanocytes via MITF to regulate the downstream pigmental genes.Sci. Agric. Sin. 2017; 50: 1334-1342
- Involvement of microphthalmia-associated transcription factor (MITF) in expression of human melanocortin-1 receptor (MC1R).Life Sci. 2002; 71: 2171-2179
- The cloning of a family of genes that encode the melanocortin receptors.Science. 1992; 257: 1248-1251
- Fifteen-year quest for microphthalmia-associated transcription factor target genes.Pigment Cell Melanoma Res. 2010; 23: 27-40
- KIT as a therapeutic target in melanoma.J. Invest. Dermatol. 2010; 130: 20-27
- Mechanisms underlying the dysfunction of melanocytes in vitiligo epidermis: role of SCF/KIT protein interactions and the downstream effector, MITF-M.J. Pathol. 2004; 202: 463-475
- C-KIT signaling depends on microphthalmia-associated transcription factor for effects on cell proliferation.PLoS One. 2011; 6: e24064
- A single UVB exposure increases the expression of functional KIT in human melanocytes by up-regulating MITF expression through the phosphorylation of p38/CREB.Arch. Dermatol. Res. 2010; 302: 283-294
Article info
Publication history
Published online: February 19, 2018
Accepted:
February 14,
2018
Received in revised form:
February 6,
2018
Received:
April 27,
2017
Identification
Copyright
© 2018 Published by Elsevier B.V. on behalf of Japanese Society for Investigative Dermatology.
