Transcription factor Glis3, a novel critical player in the regulation of pancreatic beta-cell development and insulin gene expression.
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.
Kang
Hong Soon
HS
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.
Kim
Yong-Sik
YS
ZeRuth
Gary
G
Beak
Ju Youn
JY
Gerrish
Kevin
K
Kilic
Gamze
G
Sosa-Pineda
Beatriz
B
Jensen
Jan
J
Pierreux
Christophe E
CE
Lemaigre
Frederic P
FP
Foley
Julie
J
Jetten
Anton M
AM
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
D004268:DNA-Binding Proteins; C478000:Glis3 protein, mouse; D007328:Insulin; D012097:Repressor Proteins; D015534:Trans-Activators