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

Abstract

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 ␤-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 ␤-cell neogenesis.

A feat of metabolic proportions: Pdx1 orchestrates islet development and function in the maintenance of glucose homeostasis

“…The sand rat (Psammomys obesus) is a particularly an interesting case, as Pdx1 is not normally found in islets from these animals; however, gene transfer experiments show that repletion of Pdx1 in these islets greatly enhances insulin content and glucose-stimulated insulin transcription [62]. Complete or near-complete deletion of Pdx1 in late embryonic [63] or adult mice [64] also result in a later diabetic phenotype. Although subtle developmental defects cannot be ruled out, these observations suggest a dramatically different requirement for Pdx1 gene dosage in the developing pancreas vs. the mature β cell, the latter of which may require more tightly regulated transcription and/or translation.…”

“…Based upon these studies, several mechanisms have been postulated: (a) increased β cell apoptosis via and Bcl-2), with resulting loss of downregulation of anti-apoptotic genes (Bcl XL functional cell mass [56,67], (b) loss of activity of key Pdx1 target genes whose products are involved in glucose-stimulated insulin transcription and secretion (including Glut2, glucokinase, MafA, Nkx6.1, insulin) [57,63,[68][69][70][71][72][73][74][75][76], and (d) loss of new β cell formation/regeneration [64,77]; in this regard, studies suggest that the action of glucagon-like peptide 1 (GLP1) in enhancing β cell growth and formation in the adult may rely upon activation of Pdx1 in β cells and potential precursor cell types, such as those residing within ducts [74,[78][79][80][81][82].…”

“…Although the majority of these cofactor interactions with Pdx1 are believed to enhance the activation function of Pdx1, there is the distinct possibility that certain cofactor interactions may allow Pdx1 to aid in the repression of some genes. In this regard, the well-defined repression of genes such as glucagon [63,64,70,134] and K19 [100] by Pdx1 may reflect a repression complex formed in association with corepressor molecules.…”

β-Cell regeneration: the pancreatic intrinsic faculty

“…However, Collombat and colleagues recently reported that ectopic expression of the b-cell-specific transcription factor Pax4 in mouse embryonic a-cells triggers their conversion into b-cells [74]. Conversely, downregulation of Pdx1 in bcells triggers the expression of glucagon, thus leading to the accumulation of cells coexpressing insulin and glucagon [33,75,76]; similarly, upregulation of Arx in embryonic b-cells pushes them towards the acquisition of the a-cell phenotype [77].…”

“…Conditional and transient downregulation of Pdx1 triggers diabetes within two weeks using the Pdx1-tTA knockin line crossed with TetO-Pdx1 transgenic mice [33]. After doxycyclin (DOX) removal, regeneration is induced by the re-expression of Pdx1, with increased cell proliferation and appearance of Pdx1+ and Pdx1+/insulin+ cells associated with ducts.…”