Rfx6 directs islet formation and insulin production in mice and humans.

Insulin from the beta-cells of the pancreatic islets of Langerhans controls energy homeostasis in vertebrates, and its deficiency causes diabetes mellitus. During embryonic development, the transcription factor neurogenin 3 (Neurog3) initiates the differentiation of the beta-cells and other islet cell types from pancreatic endoderm, but the genetic program that subsequently completes this differentiation remains incompletely understood. Here we show that the transcription factor Rfx6 directs islet cell differentiation downstream of Neurog3.

Activin A-induced expression of PAX4 in AR42J-B13 cells involves the increase in transactivation of E47/E12.

Pax4 is a paired-homeodomain containing transcriptional factor that controls the differentiation of pancreatic beta cells. The aim of this study was to investigate the mechanism of PAX4 expression by activin A. By reporter gene analysis using AR42J-B13 cells, in which treatment with activin A induced PAX4 mRNA expression, we identified that a short sequence located approximately 1930 bp upstream of the transcriptional start site is essential for activin A induced PAX4 promoter activation.

Hedgehog signaling regulates expansion of pancreatic epithelial cells.

Embryonic Hedgehog signaling is essential for proper tissue morphogenesis and organ formation along the developing gastrointestinal tract. Hedgehog ligands are expressed throughout the endodermal epithelium at early embryonic stages but excluded from the region that will form the pancreas. Ectopic activation of Hedgehog signaling at the onset of pancreas development has been shown to inhibit organ morphogenesis.

PAX4 gene variations predispose to ketosis-prone diabetes.

Ketosis-prone diabetes (KPD) is a rare form of type 2 diabetes, mostly observed in subjects of west African origin (west Africans and African-Americans), characterized by fulminant and phasic insulin dependence, but lacking markers of autoimmunity observed in type 1 diabetes. PAX4 is a transcription factor essential for the development of insulin-producing pancreatic beta-cells. Recently, a missense mutation (Arg121Trp) of PAX4 has been implicated in early and insulin deficient type 2 diabetes in Japanese subjects.

Neurogenin3 activates the islet differentiation program while repressing its own expression.

Expression of the proendocrine factor Neurogenin3 determines which progenitor cells in the developing pancreas will differentiate into the endocrine cells of the islets of Langerhans. To better understand how Neurogenin3 directs endocrine differentiation, we examined the mechanisms by which Neurogenin3 regulates the promoters of three transcription factor genes expressed in endocrine precursor cells: the nkx2.2 gene, the PAX4 gene, and the NEUROG3 gene, the human gene encoding Neurogenin3 itself.

Neurogenin3 and hepatic nuclear factor 1 cooperate in activating pancreatic expression of Pax4.

During fetal development, paired/homeodomain transcription factor Pax4 controls the formation of the insulin-producing beta cells and the somatostatin-producing delta cells in the islets of Langerhans in the pancreas. Targeting of Pax4 expression to the islet lineage in the fetal pancreas depends on a short sequence located approximately 2 kb upstream of the transcription initiation site of the PAX4 gene. This short sequence contains binding sites for homeodomain transcription factors PDX1 and hepatic nuclear factor (HNF)1, nuclear receptor HNF4alpha, and basic helix-loop-helix factor Neurogenin3.