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SOX9 Is a Key Player in Ultraviolet B-Induced Melanocyte Differentiation and Pigmentation

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SOX9 Is a Key Player in Ultraviolet B-Induced Melanocyte Differentiation and Pigmentation SOX9 is a key player in ultraviolet B-induced melanocyte differentiation and pigmentation Thierry Passeron*, Julio C. Valencia*, Corine Bertolotto†, Toshihiko Hoashi*, Elodie Le Pape*, Kaoruko Takahashi*, Robert Ballotti†, and Vincent J. Hearing*‡ *Pigment Cell Biology Section, Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20814; and †Unite´597, Institut National de la Sante´et de la Recherche Me´dicale, Faculte´deMe´ decine, Universite´de Nice Sophia–Antipolis, 06103 Nice, France Edited by Gertrud M. Schu¨pbach, Princeton University, Princeton, NJ, and approved July 2, 2007 (received for review May 31, 2007) SOX (SRY type HMG box) proteins are transcription factors that are (13–15). Interestingly, ectopic SOX9 expression in the neural crest predominantly known for their roles during development. During is sufficient to promote melanocytic differentiation (16), which melanocyte development from the neural crest, SOX10 regulates suggests a role for SOX9 in melanocytic development. An active microphthalmia-associated transcription factor, which controls a set transcription of SOX9 protein in melanocytes within the skin also of genes critical for pigment cell development and pigmentation, has been indirectly suggested by the presence of antibodies against including dopachrome tautomerase and tyrosinase. We report here SOX9 in the sera of vitiligo patients (17). Interestingly, the cAMP that another SOX factor, SOX9, is expressed by melanocytes in pathway, which plays a key role in melanocyte differentiation, also neonatal and adult human skin and is up-regulated by UVB exposure. has been involved in the control of SOX9 function in chondrocytes We demonstrate that this regulation is mediated by cAMP and protein (18, 19). These observations suggest that SOX9 might participate in kinase. We also show that agouti signal protein, a secreted factor the regulation of melanocyte differentiation by cAMP-elevating known to decrease pigmentation, down-regulates SOX9 expression. agents such as ␣-melanocyte-stimulating hormone (␣-MSH) or UV In adult and neonatal melanocytes, SOX9 regulates microphthal- radiation, that act, at least in part, through the cAMP pathway. In mia-associated transcription factor, dopachrome tautomerase, and the present study, we show the presence of SOX9 at the RNA and tyrosinase promoters, leading to an increase in the expression of protein levels in normal human melanocytes in vitro and in vivo.We these key melanogenic proteins and finally to a stimulation of show the up-regulation of SOX9 after UVB exposure and its pigmentation. SOX9 completes the complex and tightly regulated increased nuclear localization. We demonstrate that the effects of process leading to the production of melanin by acting at a very UVB act at least through the cAMP pathway and increased levels upstream level. This role of SOX9 in pigmentation emphasizes the of protein kinase A (PKA). We also show that agouti signal protein poorly understood impact of SOX proteins in adult tissues. (ASP), a secreted factor known to decrease pigmentation and to antagonize the signaling pathway of ␣-MSH, down-regulates SOX9 microphthalmia-associated transcription factor ͉ tyrosinase ͉ protein expression. Moreover, we demonstrate the key role of SOX9 in kinase A ͉ melanocyte-stimulating hormone ͉ agouti signal protein regulating pigmentation. Indeed, we show that SOX9 regulates MITF and DCT promoters. Overexpression of SOX9 induces an ox (SRY type HMG box) proteins are transcription factors that increase of MITF, DCT, and tyrosinase proteins, which leads to an Sbelong to the HMG box superfamily of DNA-binding proteins increased production of melanin within the cells. and play a key role during development. SOX9 belongs to the SOX-E subgroup, which includes SOX8, SOX9, and SOX10. The Results structures of these proteins show a high conservation and similar SOX9 Is Expressed in Melanocytes in Vivo. To determine whether positions of their HMG boxes (1). SOX10 has been shown to play SOX9 mRNA is expressed in human skin, we designed a specific a key role in the regulation of melanocyte differentiation (2), and probe directed against SOX9 and performed a tissue in situ mutations in SOX10 lead to Waardenburg syndrome type 4, a hybridization (TISH) study. We were able to detect a strong genetic hypomelanosis with deafness and megacolon (3). During positive staining in the epidermis with the antisense probe melanocyte development from the neural crest, SOX10 regulates whereas staining with the sense probe was negative (Fig. 1A). To the expression of microphthalmia-associated transcription factor differentiate melanocytes from keratinocytes, we coupled the (MITF), which in turn controls a set of genes critical for pigment cell TISH protocol with standard immunohistochemistry performed development and pigmentation (4). Indeed, in conjunction with with antibodies directed against MART1, a specific marker of other transcription factors, MITF regulates dopachrome tautomer- melanocytes. Melanocytes identified by MART1 also were ase (DCT), tyrosinase (the limiting enzyme for melanogenesis), and stained by the SOX9 TISH probe (Fig. 1B), demonstrating that tyrosinase-related protein 1 (TYRP1). All of these proteins are essential for the full differentiation of melanocytes and are directly Author contributions: T.P., R.B., and V.J.H. designed research; T.P. and J.C.V. performed involved in melanin synthesis. SOX10 also acts as a critical trans- research; C.B., T.H., E.L.P., and K.T. contributed new reagents/analytic tools; T.P., R.B., and activator of DCT, which MITF, on its own, is insufficient to V.J.H. analyzed data; and T.P., R.B., and V.J.H. wrote the paper. stimulate (5–7). The authors declare no conflict of interest. SOX9 has a key role in sexual determination and chondrogenesis, This article is a PNAS Direct Submission. and mutations in SOX9 can lead to campomelic dysplasia, a skeletal Abbreviations: a-LP, adult lightly pigmented; ␣-MSH, ␣-melanocyte-stimulating hormone; dysmorphology associated in most XY cases with sex reversal (8, 9). ASP, agouti signal protein; CRE, cAMP response element; CREB, CRE-binding protein; DCT, During embryonic development, the SOX9 gene becomes active in dopachrome tautomerase; MITF, microphthalmia-associated transcription factor; n-LP, all prechondrocytic mesenchymal condensations, and its expression neonatal lightly pigmented; n-DP, neonatal darkly pigmented; NHM, normal human epidermal melanocytes; n-MP, neonatal moderately pigmented; TISH, tissue in situ hybrid- is maintained at high levels in fully differentiated chondrocytes. The ization; TYRP1, tyrosinase-related protein 1; PKA, protein kinase A. direct target for SOX9 is a chondrocyte-specific enhancer in the ‡To whom correspondence may be addressed. Laboratory of Cell Biology, National Cancer gene for collagen type II (10, 11). With aging, the loss of expression Institute, National Institutes of Health, Building 37, Room 2132, MSC 4256, Bethesda, of SOX9 in some disk cells may play a role in disk degeneration by MD 20892. E-mail: [email protected]. resulting in decreased expression and production of collagen type This article contains supporting information online at www.pnas.org/cgi/content/full/ II (12). There have been increased numbers of reports showing the 0705117104/DC1. active role of SOX9 in other tissues such as heart, kidney, or brain © 2007 by The National Academy of Sciences of the USA 13984–13989 ͉ PNAS ͉ August 28, 2007 ͉ vol. 104 ͉ no. 35 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0705117104 Downloaded by guest on September 27, 2021 21 mJ/cm2 UVB and compared them with nonirradiated controls. Using RT-PCR, we showed that the expression level of SOX9 was increased1hafterUVBexposure compared with nonirradiated cells (Fig. 2A). At the protein level, an increase in SOX9 was observed starting 2 h after the UVB exposure, increased further until 8 h, and then decreased at 24 h (Fig. 2B). The stimulation of SOX9 expression was confirmed by immunoprecipitation of 35S- labeled SOX9. Finally, we compared the basal expression of SOX9 in neonatal lightly pigmented (n-LP) skin and in neonatal darkly pigmented (n-DP) skin NHM by using immunoblotting. The darker melanocytes expressed more SOX9 than did the lightly pigmented melanocytes (Fig. 2C). The Action of UVB on SOX9 Is Mediated by cAMP and PKA. The cAMP pathway plays a key role in regulating pigmentation and mediates most of the effects of UV on melanogenesis (20), so we next investigated the effect of cAMP on SOX9. After 35S metabolic labeling, NHM were exposed to 21 mJ/cm2 UVBortoforskolin,a cAMP-stimulating agent, and then SOX9 was immunoprecipitated. Treatment with either UVB or forskolin led to increased expression of SOX9 (Fig. 3A). PKA, the most important downstream target of cAMP, can be inhibited by H89. The expressions of SOX9 and SOX9 phosphorylated at S181 were both increased after UVB exposure, and in both cases, pretreatment with H89 prevented the increased expression of SOX9 by UVB (Fig. 3B). The up-regulation of SOX9 after forskolin treatment also was observed in NHM by using immunocytochemistry. Four hours after forskolin treatment, the cells were fixed and stained with SOX9 antibodies. An increased expression of SOX9 was noted in NHM Fig. 1. TISH analysis of SOX9 expression in the skin in vivo.(A) Antisense probes directed against SOX9 are present in the skin with strong nuclear staining, treated with forskolin (Fig. 4A). We also used a reconstructed skin whereas staining with the sense probe against SOX9 is negative and shows the model (MelanoDerm; MatTek, Ashland, MA) to assess the effect presence of SOX9 RNA in the skin. (B) Coupling of TISH with antisense probes of UVB on SOX9 expression in the skin. After 4 days of growth, against SOX9 and immunohistochemistry with MART1 antibody as a melanocytic MelanoDerms were exposed or not to 21 mJ/cm2 UVB. The marker shows that SOX9 is expressed in keratinocytes and in melanocytes. samples were fixed 8 h after the UV irradiation and were then double-stained with SOX9 and MART1 antibodies to identify melanocytes. The results confirmed the increased SOX9 staining in melanocytes express SOX9 in human skin in vivo.
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