title: Transcription factor Glis3, a novel critical player in the regulation of pancreatic beta-cell development and insulin gene expression.
abstract: In this study, we report that the Krüppel-like zinc finger transcription factor Gli-similar 3 (Glis3) is induced during the secondary transition of pancreatic development, a stage of cell lineage specification and extensive patterning, and that Glis3(zf/zf) mutant mice develop neonatal diabetes, evidenced by hyperglycemia and hypoinsulinemia. The Glis3(zf/zf) mutant mouse pancreas shows a dramatic loss of beta and delta cells, contrasting a smaller relative loss of alpha, PP, and epsilon cells. In addition, Glis3(zf/zf) mutant mice develop ductal cysts, while no significant changes were observed in acini. Gene expression profiling and immunofluorescent staining demonstrated that the expression of pancreatic hormones and several transcription factors important in endocrine cell development, including Ngn3, MafA, and Pdx1, were significantly decreased in the developing pancreata of Glis3(zf/zf) mutant mice. The population of pancreatic progenitors appears not to be greatly affected in Glis3(zf/zf) mutant mice; however, the number of neurogenin 3 (Ngn3)-positive endocrine cell progenitors is significantly reduced. Our study indicates that Glis3 plays a key role in cell lineage specification, particularly in the development of mature pancreatic beta cells. In addition, we provide evidence that Glis3 regulates insulin gene expression through two Glis-binding sites in its proximal promoter, indicating that Glis3 also regulates beta-cell function.
authors.affiliation: Cell Biology Section, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, 111 T. W. Alexander Drive, Research Triangle Park, NC 27709, USA.
authors.forename: Hong Soon
authors.initials: HS
authors.lastname: Kang
authors.forename: Yong-Sik
authors.initials: YS
authors.lastname: Kim
authors.forename: Gary
authors.initials: G
authors.lastname: ZeRuth
authors.forename: Ju Youn
authors.initials: JY
authors.lastname: Beak
authors.forename: Kevin
authors.initials: K
authors.lastname: Gerrish
authors.forename: Gamze
authors.initials: G
authors.lastname: Kilic
authors.forename: Beatriz
authors.initials: B
authors.lastname: Sosa-Pineda
authors.forename: Jan
authors.initials: J
authors.lastname: Jensen
authors.forename: Christophe E
authors.initials: CE
authors.lastname: Pierreux
authors.forename: Frederic P
authors.initials: FP
authors.lastname: Lemaigre
authors.forename: Julie
authors.initials: J
authors.lastname: Foley
authors.forename: Anton M
authors.initials: AM
authors.lastname: Jetten
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D004268:DNA-Binding Proteins; D017353:Gene Deletion; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D046228:Microarray Analysis; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D016335:Zinc Fingers
chemical_list: D004268:DNA-Binding Proteins; C478000:Glis3 protein, mouse; D007328:Insulin; D012097:Repressor Proteins; D015534:Trans-Activators