title: Sox10 regulates skin melanocyte proliferation by activating the DNA replication licensing factor MCM5.
abstract: BACKGROUND
  The control of cell proliferation is a fundamental aspect of tissue formation in development and regeneration. A cell type that illustrates this point particularly well is the neural crest-derived melanocyte, the pigment cell of vertebrates, as melanocytes can be followed easily during development and their pigment is directly visible in the integument of the adult. In mammals, melanocytes undergo physiological cycles of loss and proliferative regeneration during the hair cycle, and their proliferation is also critical during wound healing, repigmentation of depigmented lesions, and in melanoma formation and progression. Hence, a thorough analysis of the molecular parameters controlling melanocyte proliferation is crucial for our understanding of the physiology of this cell type both in health and disease.
  
  
  OBJECTIVE
  SOX10 is a critical regulator in melanocytes and melanoma cells, but its specific role in their proliferation is far from clear. In this study we analyze the role of SOX10 in regulating mammalian melanocyte proliferation in a mouse model.
  
  
  METHODS
  The role of SOX10 in melanoblast proliferation was analyzed in Sox10/+ mice by co-staining for melanocyte-specific markers and cell proliferation. In vitro, the role of SOX10 was studied by manipulating its levels using RNAi and analyzing the effects on DNA synthesis and cell growth and on gene expression at the RNA and protein levels.
  
  
  RESULTS
  Reduction of Sox10 gene dose led to a reduction in the number of melanoblasts. Knockdown of Sox10 in melanocytes led to inhibition of cell proliferation and a decrease in the expression of the minichromosome maintenance complex component 5 (MCM5). In fact, SOX10 directly activated MCM5 transcription by binding to conserved SOX10 consensus DNA sequences in the MCM5 promoter. Furthermore, the defect in cell proliferation could be rescued partially by overexpression of MCM5 in Sox10 knockdown melanocytes.
  
  
  CONCLUSIONS
  The results suggest that the SOX10-MCM5 axis plays an important role in controlling melanocyte proliferation. Our findings provide novel insights into the regulatory mechanisms of melanocyte proliferation and may have implications for our understanding of the roles of SOX10 and MCM5 in abnormal melanocyte proliferation disorders such as cutaneous melanoma.
authors.affiliation: Labratory of Developmental Cell Biology and Disease, School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, 325003, China; State Key Laboratory Cultivation Base and Key Laboratory of Vision Science of Ministry of Health and Zhejiang Provincial Key Laboratory of Ophthalmology, Wenzhou, 325003, China.
authors.forename: Zhongyuan
authors.initials: Z
authors.lastname: Su
authors.affiliation: Labratory of Developmental Cell Biology and Disease, School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, 325003, China.
authors.forename: Xiaozi
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Labratory of Developmental Cell Biology and Disease, School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, 325003, China.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Labratory of Developmental Cell Biology and Disease, School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, 325003, China.
authors.forename: Yipin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Labratory of Developmental Cell Biology and Disease, School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, 325003, China.
authors.forename: Shanpu
authors.initials: S
authors.lastname: Zhu
authors.affiliation: State Key Laboratory Cultivation Base and Key Laboratory of Vision Science of Ministry of Health and Zhejiang Provincial Key Laboratory of Ophthalmology, Wenzhou, 325003, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Lu
authors.affiliation: State Key Laboratory Cultivation Base and Key Laboratory of Vision Science of Ministry of Health and Zhejiang Provincial Key Laboratory of Ophthalmology, Wenzhou, 325003, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Qu
authors.affiliation: Labratory of Developmental Cell Biology and Disease, School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, 325003, China; State Key Laboratory Cultivation Base and Key Laboratory of Vision Science of Ministry of Health and Zhejiang Provincial Key Laboratory of Ophthalmology, Wenzhou, 325003, China. Electronic address: lhou@mail.eye.ac.cn.
authors.forename: Ling
authors.initials: L
authors.lastname: Hou
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D019070:Cell Lineage; D049109:Cell Proliferation; D002478:Cells, Cultured; D004261:DNA Replication / Q000235:genetics; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D008544:Melanocytes / Q000502:physiology*; D008545:Melanoma / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009432:Neural Crest / Q000196:embryology; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D055757:SOXE Transcription Factors / Q000235:genetics / Q000378:metabolism*; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology*; D000096142:Cutaneous Malignant Melanoma
chemical_list: D018797:Cell Cycle Proteins; C489424:Mcm5 protein, mouse; D034741:RNA, Small Interfering; D055757:SOXE Transcription Factors; C527924:Sox10 protein, mouse
keywords: Cell proliferation; Gene regulation; Neural crest; Pigment cell; Skin melanocytes; Transcription factor