Transcription Factor Glis3, a Novel Critical Player in the Regulation of Pancreatic β-Cell Development and Insulin Gene Expression

被引:123
作者
Kang, Hong Soon [1 ]
Kim, Yong-Sik [1 ,3 ]
ZeRuth, Gary [1 ]
Beak, Ju Youn [1 ]
Gerrish, Kevin [2 ]
Kilic, Gamze [4 ]
Sosa-Pineda, Beatriz [4 ]
Jensen, Jan [3 ]
Foley, Julie [5 ]
Jetten, Anton M. [1 ]
机构
[1] NIEHS, Cell Biol Sect, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA
[2] NIEHS, Microarray Lab Core, NIH, Res Triangle Pk, NC 27709 USA
[3] Cleveland Clin, Dept Stem Cell Biol & Regenerat Med, Lerner Res Inst, Cleveland, OH 44195 USA
[4] St Jude Childrens Res Hosp, Dept Genet & Tumor Cell Biol, Memphis, TN 38105 USA
[5] NIEHS, Lab Expt Pathol, NIH, Res Triangle Pk, NC 27709 USA
关键词
ZINC-FINGER PROTEIN; NEONATAL DIABETES-MELLITUS; FATE SPECIFICATION; ZIC GENES; DIFFERENTIATION; MAINTENANCE; MUTATIONS; IDENTIFICATION; REPRESSOR; LINEAGES;
D O I
10.1128/MCB.01259-09
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
In this study, we report that the Kruppel-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.
引用
收藏
页码:6366 / 6379
页数:14
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