SOX9 is a key player in ultraviolet B-induced melanocyte differentiation and pigmentation

Abstract

SOX (SRY type HMG box) proteins are transcription factors that are predominantly known for their roles during development. During melanocyte development from the neural crest, SOX10 regulates microphthalmia-associated transcription factor, which controls a set of genes critical for pigment cell development and pigmentation, including dopachrome tautomerase and tyrosinase. We report here that another SOX factor, SOX9, is expressed by melanocytes in neonatal and adult human skin and is up-regulated by UVB exposure. We demonstrate that this regulation is mediated by cAMP and protein kinase. We also show that agouti signal protein, a secreted factor known to decrease pigmentation, down-regulates SOX9 expression. In adult and neonatal melanocytes, SOX9 regulates microphthalmia-associated transcription factor, dopachrome tautomerase, and tyrosinase promoters, leading to an increase in the expression of these key melanogenic proteins and finally to a stimulation of pigmentation. SOX9 completes the complex and tightly regulated process leading to the production of melanin by acting at a very upstream level. This role of SOX9 in pigmentation emphasizes the poorly understood impact of SOX proteins in adult tissues.microphthalmia-associated transcription factor ͉ tyrosinase ͉ protein kinase A ͉ melanocyte-stimulating hormone ͉ agouti signal protein S ox (SRY type HMG box) proteins are transcription factors that belong to the HMG box superfamily of DNA-binding proteins and play a key role during development. SOX9 belongs to the SOX-E subgroup, which includes SOX8, SOX9, and SOX10. The structures of these proteins show a high conservation and similar positions of their HMG boxes (1). SOX10 has been shown to play a key role in the regulation of melanocyte differentiation (2), and mutations in SOX10 lead to Waardenburg syndrome type 4, a genetic hypomelanosis with deafness and megacolon (3). During melanocyte development from the neural crest, SOX10 regulates the expression of microphthalmia-associated transcription factor (MITF), which in turn controls a set of genes critical for pigment cell development and pigmentation (4). Indeed, in conjunction with other transcription factors, MITF regulates dopachrome tautomerase (DCT), tyrosinase (the limiting enzyme for melanogenesis), and tyrosinase-related protein 1 (TYRP1). All of these proteins are essential for the full differentiation of melanocytes and are directly involved in melanin synthesis. SOX10 also acts as a critical transactivator of DCT, which MITF, on its own, is insufficient to stimulate (5-7).SOX9 has a key role in sexual determination and chondrogenesis, and mutations in SOX9 can lead to campomelic dysplasia, a skeletal dysmorphology associated in most XY cases with sex reversal (8, 9). During embryonic development, the SOX9 gene becomes active in all prechondrocytic mesenchymal condensations, and its expression is maintained at high levels in fully differentiated chondrocytes. The direct target for SOX9 is a chondrocyte-specific enhancer in the gene for collagen ...

Transcription Factor SOX9 Plays a Key Role in the Regulation of Visual Cycle Gene Expression in the Retinal Pigment Epithelium

“…The direct relations reported in the RPE are regulation of Mitf and Otx2 by ␤-catenin (14) and regulation of Rdh5 by OTX2 (16). The direct relations reported in non-RPE cells are regulation of MITF by SOX9 in human skin melanocytes (67) and regulation of Sox9 by LHX2 in mouse skin keratinocytes (26) (Fig. 9).…”

Tobacco smoke–induced skin pigmentation is mediated by the aryl hydrocarbon receptor

“…When exposed to sunlight, melanocytes produce more melanins for UV protection. The activation mechanisms of melanocytes through a-melanocyte-stimulating hormone (MSH) were reported previously (9,10). The SCF/c-kit pathway is also reported to mediate UVB-induced melanogenesis via the AhR (11).…”

Microarray analysis sheds light on the dedifferentiating role of agouti signal protein in murine melanocytes via the Mc1r

“…The decrease in expression of Mitf and its downstream targets elicited by ASP may also arise at least in part from the downregulation of the SRY HMG box Sox9 (56) and from the inactivation of PKA. The microarray dataset reveals the up-regulation by ASP of genes encoding (i) Prkar1a and Prkar1b, 2 regulatory subunits of PKA inactivating its catalytic domains; (ii) Pkia and Pkib, 2 competitive inhibitors of PKA which interact with the catalytic subunit of the enzyme (both down-regulated by ␣MSH); and (iii) Cri, the inhibitor of Crebbp (or its homologue P300), which is required in the transcriptional activation complex induced by PKA.…”