Disease relevance of Pax4

• Activation of Pax4 resulted in the expression of the late-stage transcription factors, including Pax6, Isl-1, and MafA, and generated a gene expression profile for WB-1A cells similar to that of functional rat insulinoma INS-1 cells [1].

High impact information on Pax4

• As mice lacking Pax4 and Pax6 fail to develop any mature endocrine cells, we conclude that both Pax genes are required for endocrine fate in the pancreas [2].
• Pancreas development is known to be abolished in Pdx1-mutant mice and Pax4 mutants lack insulin-producing beta-cells [2].
• We propose that the early expression of Pax4 in a subset of endocrine progenitors is essential for the differentiation of the beta and delta cell lineages [3].
• Our study indicates a requirement of Arx for alpha-cell fate acquisition and a repressive action on beta-and delta-cell destiny, which is exactly the opposite of the action of Pax4 in endocrine commitment [4].
• The expansion of ghrelin-producing cells at the expense of beta cells may be a general phenomenon, because we demonstrate that Pax4 mutant mice display a similar phenotype [5].

Biological context of Pax4

• By inactivating the homeobox gene Pax4, we previously demonstrated that its function is required for the formation of mature insulin-producing cells [6].
• We conclude that constitutive expression of Pax4 in combination with histotypic cultivation facilitates ES cell differentiation into the pancreatic lineage, which leads to the formation of islet-like spheroid structures that produce increased levels of insulin [7].
• In this study, we characterized the DNA-binding and transactivation properties of mouse Pax4 [8].
• We isolated and sequenced a 2.4-kb mouse genomic DNA fragment containing the 5' flanking sequence of Pax4 and identified a previously unrecognized intron [9].
• Cloning of the mouse Pax4 gene promoter and identification of a pancreatic beta cell specific enhancer [9].

Anatomical context of Pax4

• We propose that the antagonistic functions of Arx and Pax4 for proper islet cell specification are related to the pancreatic levels of the respective transcripts [4].
• The concerted activities of Pax4 and Nkx2.2 are essential to initiate pancreatic beta-cell differentiation [6].
• Here, we show that during pancreas ontogeny, Pax4 is expressed in differentiating endocrine cells, including beta cells [6].
• Expression of Pax4 in embryonic stem cells promotes differentiation of nestin-positive progenitor and insulin-producing cells [7].
• As Pax4 promotes late-stage beta-cell differentiation and maturation, we generated lentiviral vector (LV) containing mouse Pax4 gene and developed two hepatic cell lines expressing Pax4 in the absence (WB-2 cells) or presence (WB-1A cells) of Pdx1-VP16, via LV-mediated gene transfer [1].

Associations of Pax4 with chemical compounds

• In response to glucose, Pax4(+) and wild-type ES-derived cells release insulin [7].
• 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 [10].

Physical interactions of Pax4

• We believe that Pax-4 can act as a Pax-6 "repressor," due to the competition for binding sites and lower transactivation potential of Pax-4 [11].

Regulatory relationships of Pax4

• The overexpression of Pax4 in HIT-T15 cells dose dependently inhibited the basal transcriptional activity as well as Pax6-induced activity [8].
• The Pax4 gene is expressed in the early pancreas, but is later restricted to beta cells [3].

Other interactions of Pax4

• This role of Pax4 appears to be accomplished via its genetic interaction with another homeobox gene, Nkx2.2 [6].
• We do not however find any expression of the late-stage genes (Pax4, Pax6, Isl-1, and MafA) related to beta-cell development, and the cells do not secrete insulin upon the glucose challenge [12].
• In contrast, Pax-4 had no effect on Cdx-2/3 or HNF3alpha mediated transcriptional activation [13].
• 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 [14].
• During ES cell differentiation, transcript levels of genes characteristic of early and mature beta cells including Pdx1, Pax4, insulin and islet amyloid pancreatic peptide are up regulated [15].

Analytical, diagnostic and therapeutic context of Pax4

• PAX4 transcriptional regulation apparently plays a role only early in islet development, since Pax4 mRNA as determined by reverse transcriptase PCR peaks at embryonic day 13.5 in the fetal mouse pancreas and is undetectable in adult islets [16].
• Functional Pax4 protein expression in WB-2 and WB-1A cells was confirmed by electrophoretic mobility shift assay and Pdx1-VP16 protein expression in WB-1 and WB-1A cells was confirmed by Western blotting [1].
• Southern blot analysis suggested that the mouse Pax-4 gene exists as a single copy in the genome [17].
• Molecular cloning of mouse paired-box-containing gene (Pax)-4 from an islet beta cell line and deduced sequence of human Pax-4 [17].
• The gene-targeting experiments revealed that Pax-4 and Pax-6 cannot substitute for each other in tissue with overlapping expression of both genes [11].

References