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Diabetes 54:2586-2595, 2005
© 2005 by the American Diabetes Association, Inc.

Conditional Expression Demonstrates the Role of the Homeodomain Transcription Factor Pdx1 in Maintenance and Regeneration of ß-Cells in the Adult Pancreas

Andrew M. Holland1, L. Jorge Góñez1, Gaetano Naselli1, Raymond J. MacDonald2, and Leonard C. Harrison1

1 Autoimmunity and Transplantation Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
2 Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas

The homeodomain transcription factor Pdx1 is essential for pancreas development. To investigate the role of Pdx1 in the adult pancreas, we employed a mouse model in which transcription of Pdx1 could be reversibly repressed by administration of doxycycline. Repression of Pdx1 in adult mice impaired expression of insulin and glucagon, leading to diabetes within 14 days. Pdx1 repression was associated with increased cell proliferation predominantly in the exocrine pancreas and upregulation of genes implicated in pancreas regeneration. Following withdrawal of doxycycline and derepression of Pdx1, normoglycemia was restored within 28 days; during this period, Pdx1+/Ins+ and Pdx+/Ins– cells were observed in association with the duct epithelia. These findings confirm that Pdx1 is required for ß-cell function in the adult pancreas and indicate that in the absence of Pdx1 expression, a regenerative program is initiated with the potential for Pdx1-dependent ß-cell neogenesis.

Address correspondence and reprint requests to Leonard C. Harrison, Autoimmunity and Transplantation Division, Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia. E-mail: harrison{at}wehi.edu.au

Abbreviations: DAPI, 4',6'-diamidine-2'-phenylindole dihydrochloride


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