title: MafA is required for postnatal proliferation of pancreatic β-cells.
abstract: The postnatal proliferation and maturation of insulin-secreting pancreatic β-cells are critical for glucose metabolism and disease development in adults. Elucidation of the molecular mechanisms underlying these events will be beneficial to direct the differentiation of stem cells into functional β-cells. Maturation of β-cells is accompanied by increased expression of MafA, an insulin gene transcription factor. Transcriptome analysis of MafA knockout islets revealed MafA is required for the expression of several molecules critical for β-cell function, including Glut2, ZnT8, Granuphilin, Vdr, Pcsk1 and Urocortin 3, as well as Prolactin receptor (Prlr) and its downstream target Cyclin D2 (Ccnd2). Inhibition of MafA expression in mouse islets or β-cell lines resulted in reduced expression of Prlr and Ccnd2, and MafA transactivated the Prlr promoter. Stimulation of β-cells by prolactin resulted in the phosphorylation and translocation of Stat5B and an increased nuclear pool of Ccnd2 via Prlr and Jak2. Consistent with these results, the loss of MafA resulted in impaired proliferation of β-cells at 4 weeks of age. These results suggest that MafA regulates the postnatal proliferation of β-cells via prolactin signaling.
authors.affiliation: Department of Metabolic Disorders, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan; Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Koki
authors.initials: K
authors.lastname: Eto
authors.affiliation: Department of Metabolic Disorders, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Nishimura
authors.affiliation: Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, Tennodai, Tsukuba, Ibaraki, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Oishi
authors.affiliation: Department of Metabolic Disorders, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Haruhide
authors.initials: H
authors.lastname: Udagawa
authors.affiliation: Department of Metabolic Disorders, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Kawaguchi
authors.affiliation: Department of Metabolic Disorders, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Hiramoto
authors.affiliation: Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Toshiyoshi
authors.initials: T
authors.lastname: Fujiwara
authors.affiliation: Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, Tennodai, Tsukuba, Ibaraki, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Takahashi
authors.affiliation: Department of Metabolic Disorders, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Yasuda
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002460:Cell Line; D049109:Cell Proliferation; D056742:Cyclin D2 / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism; D051473:Maf Transcription Factors, Large / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D051381:Rats; D011981:Receptors, Prolactin / Q000235:genetics; D015398:Signal Transduction; D059467:Transcriptome
chemical_list: D056742:Cyclin D2; D051473:Maf Transcription Factors, Large; C485160:Mafa protein, mouse; D011981:Receptors, Prolactin