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Molecular and Cellular Biology, August 2009, p. 4417-4430, Vol. 29, No. 16
0270-7306/09/$08.00+0     doi:10.1128/MCB.01622-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Regulation of Pancreatic Juxtaductal Endocrine Cell Formation by FoxO1{triangledown}

Tadahiro Kitamura,1,2 Yukari Ido Kitamura,1,2 Masaki Kobayashi,2 Osamu Kikuchi,2 Tsutomu Sasaki,2 Ronald A. DePinho,3 and Domenico Accili1*

Department of Medicine, College of Physicians & Surgeons of Columbia University, New York, New York 10032,1 Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma 371-8512, Japan,2 Center for Applied Cancer Science, Departments of Medical Oncology, Medicine, and Genetics, and Belfer Institute for Innovative Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 021153

Received 16 October 2008/ Returned for modification 27 January 2009/ Accepted 22 May 2009

An understanding of the mechanisms that govern pancreatic endocrine cell ontogeny may offer strategies for their somatic replacement in diabetic patients. During embryogenesis, transcription factor FoxO1 is expressed in pancreatic progenitor cells. Subsequently, it becomes restricted to β cells and to a rare population of insulin-negative juxtaductal cells (FoxO1+ Ins–). It is unclear whether FoxO1+ Ins– cells give rise to endocrine cells. To address this question, we first evaluated FoxO1's role in pancreas development using gain- and loss-of-function alleles in mice. Premature FoxO1 activation in pancreatic progenitors promoted {alpha}-cell formation but curtailed exocrine development. Conversely, FoxO1 ablation in pancreatic progenitor cells, but not in committed endocrine progenitors or terminally differentiated β cells, selectively increased juxtaductal β cells. As these data indicate an involvement of FoxO1 in pancreatic lineage determination, FoxO1+ Ins– cells were clonally isolated and assayed for their capacity to undergo endocrine differentiation. Upon FoxO1 activation, FoxO1+ Ins– cultures converted into glucagon-producing cells. We conclude that FoxO1+ Ins– juxtaductal cells represent a hitherto-unrecognized pancreatic cell population with in vitro capability of endocrine differentiation.

* Corresponding author. Mailing address: 1150 St. Nicholas Ave., New York, NY 10032. Phone: (212) 851-5332. Fax: (212) 851-5331. E-mail: da230{at}columbia.edu

{triangledown} Published ahead of print on 8 June 2009.

Molecular and Cellular Biology, August 2009, p. 4417-4430, Vol. 29, No. 16
0270-7306/09/$08.00+0     doi:10.1128/MCB.01622-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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