Development - Melanocyte development and pigmentation

Melanocyte development and pigmentation

Melanocytes are cells located in the epidermis that are responsible for producing melanin. This process is known as melanogenesis.

There are 3 main pathways regulating melanogenesis: via cyclic adenosine monophosphate (cAMP), via Protein kinase C, beta (PKC-beta) and via Nitric oxide (NO).

cAMP plays a key role in the control of pigmentation. Pigmentation in mammals is stimulated mainly by Alpha-melanocyte stimulating hormone (alpha-MSH) and Adrenocorticotropic hormone (ACTH). Both of them can bind to the Melanocortin 1 receptor (MC1R), which is coupled to G-protein alpha-s and stimulates Adenylate cyclase, resulting in cAMP production and cAMP-dependent protein kinase (PKA) activation [1]. PKA, in turn, phosphorylates and activates cAMP response element-binding protein 1 (CREB1). Phosphorylated CREB1 interacts with CREB binding protein (CBP) to activate the expression of microphthalmia-associated transcription factor (MITF) throughout the CRE in the promoter region of the gene [2], [3]. MITF, in turn, regulates transcription of genes coding MRPs through interactions with M- and E-boxes present in the promoter regions of Tyrosinase (TYRO), Tyrosinase-related protein 1 (TYRP1), and Tyrosinase-related protein 2 (TYRP2). Taken together, these complex molecular processes finally allow a fine tuning of melanocyte differentiation leading to melanin synthesis [3], [4].

The transcription factors Paired box 3 P (PAX3) and SRY (sex determining region Y)-box 10 (SOX10) transactivate the MITF gene promoter and regulate the TYRP1 and TYRP2 respectively. Additionally, SOX10 directly binds to TYRP2 promoter and enhances its expression [5], [6].

WNT signaling pathway plays a critical role in melanocyte development. Wingless-related MMTV integration site 3A (WNT3A) binds to the members of the seven transmembrane receptor Frizzled (Frizzled) and activates the canonical WNT pathway, which results in Catenin beta 1 (Beta-catenin) translocation to the nucleus. Beta-catenin and Lymphoid enhancer-binding factor 1 (Lef-1) are recruited to the MITF gene promoter and up-regulate MITF expression, which in turn leads to pigment cell differentiation [7]. In addition, Beta-catenin associates with MITF and activates transcription of MITF target genes [8].

MITF regulates not only the expression of enzymes involved in melanin synthesis, but also the expression of MC1R that can initiate melanogenesis via cAMP pathway [9].

cAMP can regulate another signaling pathways that are also involved in the control of melanogenesis. cAMP inhibits Phosphatidylinositol 3-kinase (PI3K) and v-akt murine thymoma viral oncogene homolog (AKT(PKB)) and promotes an activation of Glycogen synthase kinase 3 beta (GSK3 beta). GSK3 beta, by phosphorylation of MITF on serine 298, increases its binding to the M-box of the TYRO promoter, leading to stimulation of tyrosinase expression [10].

Additionally, cAMP stimulates v-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-Ras)/ Mitogen-activated protein kinases 1 and 3 (ERK1/2) pathway. In this pathway, cAMP activates the H-Ras/ v-Raf murine sarcoma viral oncogene homolog B1 (B-Raf)/ Mitogen-activated protein kinase kinase 1 (MEK1 (MAP2K1))/ ERK1/2/ Ribosomal protein S6 kinase, 90kDa, polypeptide 1 (p90RSK1) cascade. Phosphorylation of MITF on serine by p90RSK1 promotes its degradation that prevents an excessive production of melanin synthesis [10].

Kit ligand (MGF)/ v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (c-Kit) signaling regulates pigmentation in melanocytes by targeting MITF simultaneously for activation and proteolytic degradation via 2 cascades: Growth factor receptor-bound protein 2 (GRB2)/ : Son of sevenless homolog (SOS)/ H-RAS/ B-Raf/ MEK1 (MAP2K1)/ ERK1/2/ p90RSK1 and PI3K/ AKT/ GSK3 beta [11], [12], [13].

Another signal transduction pathway important in the regulation of melanogenesis is represented by PKC-beta [14]. 1,2-Diacylglycerol (DAG) stimulated by UV irradiation can activate this pathway [15]. Nucleotide binding protein, beta polypeptide 2-like 1 (RACK1), in turn, anchors activated PKC-beta on the melanosome membrane, thus allowing phosphorylate tyrosinase [14].

UV irradiation as well activates Guanylate cyclase through stimulation of NO synthase, thus leading to increase cyclic GMP. Cyclic GMP, in turn, activates Protein kinase G1 and stimulates melanogenesis [16].

References:

1. Gantz I, Fong TM
   The melanocortin system. American journal of physiology. Endocrinology and metabolism 2003 Mar;284(3):E468-74
2. Sato S, Roberts K, Gambino G, Cook A, Kouzarides T, Goding CR
   CBP/p300 as a co-factor for the Microphthalmia transcription factor. Oncogene 1997 Jun 26;14(25):3083-92
3. Bertolotto C, Abbe P, Hemesath TJ, Bille K, Fisher DE, Ortonne JP, Ballotti R
   Microphthalmia gene product as a signal transducer in cAMP-induced differentiation of melanocytes. The Journal of cell biology 1998 Aug 10;142(3):827-35
4. Bertolotto C, Buscà R, Abbe P, Bille K, Aberdam E, Ortonne JP, Ballotti R
   Different cis-acting elements are involved in the regulation of TRP1 and TRP2 promoter activities by cyclic AMP: pivotal role of M boxes (GTCATGTGCT) and of microphthalmia. Molecular and cellular biology 1998 Feb;18(2):694-702
5. Bondurand N, Pingault V, Goerich DE, Lemort N, Sock E, Le Caignec C, Wegner M, Goossens M
   Interaction among SOX10, PAX3 and MITF, three genes altered in Waardenburg syndrome. Human molecular genetics 2000 Aug 12;9(13):1907-17
6. Ludwig A, Rehberg S, Wegner M
   Melanocyte-specific expression of dopachrome tautomerase is dependent on synergistic gene activation by the Sox10 and Mitf transcription factors. FEBS letters 2004 Jan 2;556(1-3):236-44
7. Takeda K, Yasumoto K, Takada R, Takada S, Watanabe K, Udono T, Saito H, Takahashi K, Shibahara S
   Induction of melanocyte-specific microphthalmia-associated transcription factor by Wnt-3a. The Journal of biological chemistry 2000 May 12;275(19):14013-6
8. Schepsky A, Bruser K, Gunnarsson GJ, Goodall J, Hallsson JH, Goding CR, Steingrimsson E, Hecht A
   The microphthalmia-associated transcription factor Mitf interacts with beta-catenin to determine target gene expression. Molecular and cellular biology 2006 Dec;26(23):8914-27
9. Aoki H, Moro O
   Involvement of microphthalmia-associated transcription factor (MITF) in expression of human melanocortin-1 receptor (MC1R). Life sciences 2002 Sep 20;71(18):2171-9
10. Khaled M, Larribere L, Bille K, Aberdam E, Ortonne JP, Ballotti R, Bertolotto C
    Glycogen synthase kinase 3beta is activated by cAMP and plays an active role in the regulation of melanogenesis. The Journal of biological chemistry 2002 Sep 13;277(37):33690-7
11. Hemesath TJ, Price ER, Takemoto C, Badalian T, Fisher DE
    MAP kinase links the transcription factor Microphthalmia to c-Kit signalling in melanocytes. Nature 1998 Jan 15;391(6664):298-301
12. Price ER, Ding HF, Badalian T, Bhattacharya S, Takemoto C, Yao TP, Hemesath TJ, Fisher DE
    Lineage-specific signaling in melanocytes. C-kit stimulation recruits p300/CBP to microphthalmia. The Journal of biological chemistry 1998 Jul 17;273(29):17983-6
13. Widlund HR, Fisher DE
    Microphthalamia-associated transcription factor: a critical regulator of pigment cell development and survival. Oncogene 2003 May 19;22(20):3035-41
14. Park HY, Wu H, Killoran CE, Gilchrest BA
    The receptor for activated C-kinase-I (RACK-I) anchors activated PKC-beta on melanosomes. Journal of cell science 2004 Jul 15;117(Pt 16):3659-68
15. Gilchrest BA, Park HY, Eller MS, Yaar M
    Mechanisms of ultraviolet light-induced pigmentation. Photochemistry and photobiology 1996 Jan;63(1):1-10
16. Roméro-Graillet C, Aberdam E, Biagoli N, Massabni W, Ortonne JP, Ballotti R
    Ultraviolet B radiation acts through the nitric oxide and cGMP signal transduction pathway to stimulate melanogenesis in human melanocytes. The Journal of biological chemistry 1996 Nov 8;271(45):28052-6