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Molecular and Cellular Biology, December 2009, p. 6366-6379, Vol. 29, No. 24
0270-7306/09/$08.00+0     doi:10.1128/MCB.01259-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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

Hong Soon Kang,1,{dagger} Yong-Sik Kim,1,2,{dagger} Gary ZeRuth,1 Ju Youn Beak,1 Kevin Gerrish,3 Gamze Kilic,4 Beatriz Sosa-Pineda,4 Jan Jensen,2 Julie Foley,5 and Anton M. Jetten1*

Cell Biology Section, Division of Intramural Research,1 Microarray Lab Core, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709,3 Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195,2 Department of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105,4 Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 277095

Received 17 September 2009/ Returned for modification 22 September 2009/ Accepted 25 September 2009

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 Glis3zf/zf mutant mice develop neonatal diabetes, evidenced by hyperglycemia and hypoinsulinemia. The Glis3zf/zf mutant mouse pancreas shows a dramatic loss of β and {delta} cells, contrasting a smaller relative loss of {alpha}, PP, and {varepsilon} cells. In addition, Glis3zf/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 Glis3zf/zf mutant mice. The population of pancreatic progenitors appears not to be greatly affected in Glis3zf/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 β 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 β-cell function.

* Corresponding author. Mailing address: National Institute of Environmental Health Sciences, National Institutes of Health, 111 T. W. Alexander Drive, Research Triangle Park, NC 27709. Phone: (919) 541-2768. Fax: (919) 541-4133. E-mail: jetten{at}niehs.nih.gov

{triangledown} Published ahead of print on 5 October 2009.

{dagger} These authors contributed equally to this work.

Molecular and Cellular Biology, December 2009, p. 6366-6379, Vol. 29, No. 24
0270-7306/09/$08.00+0     doi:10.1128/MCB.01259-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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