Luc St-Onge

Pax 4 and 6 regulate gastrointestinal endocrine cell development

The mechanisms behind the cell-specific and compartmentalized expression of gut and pancreatic hormones is largely unknown. We hereby report that deletion of the Pax 4 gene virtually eliminates duodenal and jejunal hormone-secreting cells, as well as serotonin and somatostatin cells of the distal stomach, while deletion of the Pax 6 gene eliminates duodenal GIP cells as well as gastrin and somatostatin cells of the distal stomach. Thus, together, these two genes regulate the differentiation of all proximal gastrointestinal endocrine cells and reflect common pathways for pancreatic and gastrointestinal endocrine cell differentiation.

Transcription factor expression during pancreatic islet regeneration.

Recent studies by a number of laboratories have identified transcription factors that are involved in pancreatic development. Indeed, marked abnormalities in pancreatic development result from deficiencies in these molecules, which include, among others, PDX-1, islet-1 (Isl-1), and Pax-6. These studies have prompted us to evaluate the expression of Isl-1 and Pax-6 in the pancreas of the interferon-gamma (IFNgamma) transgenic mouse, which exhibits new islet growth and expansion of ducts throughout the life of the animal. We have previously demonstrated that PDX-1 is strikingly expressed in the ducts of the IFNgamma transgenic mouse. This latter observation compelled us to examine expression of hepatocyte nuclear factor-3beta (HNF3beta), which mediates PDX-1 gene transcription, in the IFNgamma transgenic pancreas as well. As a result of these studies, we now demonstrate marked expression of these transcription factors in the pancreatic ducts of IFNgamma transgenic mice. These data suggest a role for these transcription factors during pancreatic regeneration in the IFNgamma transgenic mouse.

Role of PAX genes in endoderm-derived organs.

Pax genes, which encode a family of transcription factors, are essentially required for the formation of several tissues from all germ layers in the mammalian embryo. Specifically, in organogenesis, they are involved in triggering early events of cell differentiation. The differentiation of endoderm-derived endocrine pancreas is mediated through Pax4 and Pax6. In the thyroid gland, Pax8 is essential for the formation of thyroxine-producing follicular cells, also of endodermal origin. The analysis of loss-of-function mutants revealed a common function of Pax genes in organogenesis.

The role of Pax genes during murine development

Members of the Pax gene family exhibit distinct temporal and spatial expression patterns during murine embryogenesis. Their unique expression in the central nervous system implies a role in the regionalization of the spinal cord and early brain. Pax proteins are localized in the cell nucleus and possess a DNA-binding activity. This makes them good candidates for transcriptional regulator of developmental processes. Mutations in three Pax genes have been associated with three mouse mutants and two human diseases indicating that their activity is necessary for proper development of the embryo

IFN-γ overexpression within the pancreas is not sufficient to rescue Pax4, Pax6, and Pdx-1 mutant mice from death

In the presence of interferon-&ggr; (IFN-&ggr;), pancreatic ductal epithelial cells grow continuously, and islets undergo neogenesis. To determine whether these new islets are derived from conventional precursors, we tested whether IFN-&ggr; can complement the loss of transcription factors known to regulate pancreatic development. We analyzed the effect of a transgene on lethality in mice lacking the transcription factors Pax4, Pax6, or Pdx-1, by intercrossing such mice with transgenic mice whose pancreatic cells make IFN-&ggr; (ins-IFN-&ggr; mice). However, IFN-&ggr; expression did not rescue these mice from the lethal mutations, because no homozygous knockout mice carrying the IFN-&ggr; transgene survived, despite the survival of all other hemizygous gene combinations. This outcome demonstrates that the pathway for IFN-&ggr; regeneration requires the participation of Pax4, Pax6, and Pdx-1. We conclude that the striking islet regeneration observed in the ins-IFN-&ggr; NOD strain is regulated by the same transcription factors that control initial pancreatic development.