The Ectopic Expression of Pax4 in the Mouse Pancreas Converts Progenitor Cells into α and Subsequently β Cells

We have previously reported that the loss of Arx and/or Pax4 gene activity leads to a shift in the fate of the different endocrine cell subtypes in the mouse pancreas, without affecting the total endocrine cell numbers. Here, we conditionally and ectopically express Pax4 using different cell-specific promoters and demonstrate that Pax4 forces endocrine precursor cells, as well as mature Beta cells, to adopt a Beta cell destiny. This results in a glucagon deficiency that provokes a compensatory and continuous glucagon+ cell neogenesis requiring the re-expression of the proendocrine gene Ngn3. However, the newly formed Beta cells fail to correct the hypoglucagonemia since they subsequently acquire a Beta cell phenotype upon Pax4 ectopic expression. Notably, this cycle of neogenesis and redifferentiation caused by ectopic expression of Pax4 in Beta cells is capable of restoring a functional Beta cell mass and curing diabetes in animals that have been chemically depleted of Beta cells.