The homeodomain protein IDX-1 increases after an early burst of proliferation during pancreatic regeneration.

Abstract

Islet duodenal homeobox 1 (IDX-1/PF-1/STF-1/PDX-1), a homeodomain protein that transactivates the insulin promoter, has been shown by targeted gene ablation to be required for pancreatic development. After 90% pancreatectomy (Px), the adult pancreas regenerates in a process recapitulating embryonic development, starting with a burst of proliferation in the epithelium of the common pancreatic duct. In this model, IDX-1 mRNA was detected by semiquantitative reverse transcription-polymerase chain reaction in total RNA from isolated common pancreatic ducts at levels 10% of those of isolated islets. The IDX-1 mRNA levels were not significantly different for common pancreatic ducts of Px, sham Px, and unoperated rats and did not change with time after surgery. By immunoblot analysis, IDX-1 protein was only faintly detected in these ducts 1 and 7 days after Px or sham Px but was easily detected at 2 and 3 days after Px. Similarly, IDX-1 immunostaining was barely detectable in sham or unoperated ducts but was strong in ducts at 2-3 days after Px. The increase of IDX-1 immunostaining followed that of BrdU incorporation (proliferation). These results indicate a posttranscriptional regulation of the IDX-1 expression in ducts. In addition, islets isolated 3-7 d after Px showed higher IDX-1 protein expression than control islets. Thus, in pancreatic regeneration IDX-1 is upregulated in newly divided ductal cells as well as in islets. The timing of enhanced expression of IDX-1 implies that IDX-1 is not important in the initiation of regeneration but may be involved in the differentiation of ductal cells to beta-cells.

Zebrafish pdx1 morphant displays defects in pancreas development and digestive organ chirality, and potentially identifies a multipotent pancreas progenitor cell

“…As a result, pdx1 mutants lack functional pancreatic tissue (Jonsson et al, 1994;Offield et al, 1996), and it has been suggested that pdx1 regulates pancreatic stem cell function. Consistent with this hypothesis, pdx1 expression is markedly increased in proliferating ductular cells during pancreatic regeneration (Kritzik et al, 1999;Sharma et al, 1999).…”

“…1Z), as in identically staged wild-type zebrafish (Fig. 1Y) and the regenerating pancreas of mammals (Sharma et al, 1999).…”

“…1Q-X). To determine whether the mechanism underlying pancreatic recovery resembled mammalian pancreatic regeneration (Kritzik et al, 1999;Sharma et al, 1999), we analyzed cell proliferation in 48, 60, and 72 hpf pdx1 morphants using 5-bromo-2Ј-deoxyuridine immunohistochemistry. These data revealed that proliferating cells in the pancreas of pdx1 morphants were present within tissue surrounding the islet in the region of the developing exocrine pancreas but never within the islet (Fig.…”

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

“…Activation of Pdx1 in duct cells of the pancreas has also been observed following partial pancreatectomy in mice [85] and in insulin resistant Zucker fatty (ZF) rats [83]. Importantly in this regard, Pdx1 expression is often observed in proliferating duct cells [77,94,95], and such cells have been suggested to serve as substrate for β cell neogenesis, particularly in cases of adaptive hyperplasia or pancreas regeneration [92,[96][97][98][99]. A recent study suggests that Pdx1, in complex with TALE transcription factors, negatively regulates the duct-specific keratin 19 gene in mature duct cells [100].…”

“…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].…”