Transcriptional profiling shows altered expression of wnt pathway- and lipid metabolism-related genes as well as melanogenesis-related genes in melasma.
ABSTRACT Melasma is a commonly acquired hyperpigmentary disorder of the face, but its pathogenesis is poorly understood and its treatment remains challenging. We conducted a comparative histological study on lesional and perilesional normal skin to clarify the histological nature of melasma. Significantly, higher amounts of melanin and of melanogenesis-associated proteins were observed in the epidermis of lesional skin, and the mRNA level of tyrosinase-related protein 1 was higher in lesional skin, indicating regulation at the mRNA level. However, melanocyte numbers were comparable between lesional and perilesional skin. A transcriptomic study was undertaken to identify genes involved in the pathology of melasma. A total of 279 genes were found to be differentially expressed in lesional and perilesional skin. As was expected, the mRNA levels of a number of known melanogenesis-associated genes, such as tyrosinase, were found to be elevated in lesional skin. Bioinformatics analysis revealed that the most lipid metabolism-associated genes were downregulated in lesional skin, and this finding was supported by an impaired barrier function in melasma. Interestingly, a subset of Wnt signaling modulators, including Wnt inhibitory factor 1, secreted frizzled-related protein 2, and Wnt5a, were also found to be upregulated in lesional skin. Immunohistochemistry confirmed the higher expression of these factors in melasma lesions.
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ABSTRACT: The orphan Leucine-rich repeat G protein-coupled receptor 5 (LGR5/GPR49), a target of Wnt signaling, is a marker of adult intestinal stem cells (SC). However, neither its function in the adults, nor during development of the intestine have been addressed yet. In this report, we investigated the role of LGR5 during ileal development by using LGR5 null/LacZ-NeoR knock-in mice. X-gal staining experiments showed that, after villus morphogenesis, Lgr5 expression becomes restricted to dividing cells clustered in the intervillus region and is more pronounced in the distal small intestine. At day E18.5, LGR5 deficiency leads to premature Paneth cell differentiation in the small intestine without detectable effects on differentiation of other cell lineages, nor on epithelial cell proliferation or migration. Quantitative RT-PCR experiments showed that expression from the LGR5 promoter was upregulated in LGR5-null mice, pointing to the existence of an autoregulatory negative feedback loop in intact animals. This deregulation was associated with overexpression of Wnt target genes in the intervillus epithelium. Transcriptional profiling of mutant mice ileums revealed that LGR5 function is associated with expression of SC and SC niche markers. Together, our data identify LGR5 as a negative regulator of the Wnt pathway in the developing intestine.Developmental Biology 05/2009; 331(1):58-67. · 3.87 Impact Factor
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ABSTRACT: Background The pathogenesis of melasma has not yet been clearly demonstrated. We tried to determine whether the stem cell factor (SCF) and its receptor c-kit are involved in the mechanism of hyperpigmentation of melasma because this factor is highly implicated in the stimulation of melanocyte function in vitro and in vivo.Objectives The present study was conducted to investigate the expression of SCF and c-kit on the lesions of melasma compared with nonlesional skin.Patients/methods Skin samples were obtained from lesional and nonlesional facial skin of 60 Korean women with melasma. Immunohistochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR) analysis was performed to determine the expression of SCF and c-kit in melasma.Results The expression of SCF was significantly increased at the lesional dermis compared with nonlesional dermis. However, there was no significant difference in the expression of SCF in lesional and nonlesional epidermis. The expression of c-kit was significantly increased at lesional epidermis compared with nonlesional skin. RT-PCR of SCF and c-kit mRNAs demonstrated increased expression of both types of transcripts in the lesional skin compared with nonlesional skin.Conclusions These results suggest that the increased expression of SCF in the dermis and of c-kit in the epidermis play an important role in the mechanism of hyperpigmentation in melasma.British Journal of Dermatology 03/2006; 154(6):1094 - 1099. · 3.76 Impact Factor
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ABSTRACT: Complexion coloration in humans is primarily regulated by the amount and type of melanin synthesized by the epidermal melanocyte. However, additional and equally contributing factors consist of (1) efficient transfer of melanin from the melanocytes to the neighboring keratinocytes and (2) distribution and degradation of the transferred melanosomes by the recipient keratinocytes. Once synthesized in the cell body of the epidermal melanocyte, pigmented melanosomes are translocated down the dendrites and captured at the dendritic tips via various cytoskeletal elements. Molecules recently identified that participate in this process consist of Rab27a, myosin-Va and melanophilin. Eventually, these peripherally localized melanosomes are transferred to keratinocytes by a presently undefined mechanism. The protease-activated receptor-2 (PAR-2) and unidentified surface lectins and glycoproteins facilitate this transfer process. Once incorporated into the keratinocytes, melanosomes are distributed individually or as clusters, aggregated towards the apical pole of the nucleus, and degraded as the keratinocytes undergo terminal differentiation and desquamation. Ultraviolet irradiation (UVR) can modulate the process of melanosome transfer from the melanocytes to the keratinocytes. UVR can upregulate expression of PAR-2 and lectin-binding receptors and increase phagocytic activity of cultured keratinocytes. Therefore, many cellular and molecular events that occur after melanogenesis contribute to skin color.Experimental Dermatology 02/2003; 12 Suppl 2:5-12. · 3.58 Impact Factor