Pax4 acts as a key player in pancreas development and plasticity

•Pax4 promotes the β- and δ-cell fate during pancreas morphogenesis.•Pax4 misexpression in α-cells leads to their conversion into β-like cells.•Pax4 converts α-cells into β-like cells through the inhibition of Arx expression.•Pax4 represents a target of interest for β-cell regeneration in diabetic patients. The embryonic development of the pancreas is orchestrated by a complex and coordinated transcription factor network. Neurogenin3 (Neurog3) initiates the endocrine program by activating the expression of additional transcription factors driving survival, proliferation, maturation and lineage allocation of endocrine precursors. Among the direct targets of Neurog3, Pax4 appears as one of the key regulators of β-cell specification. Indeed, mice lacking Pax4 die a few days postpartum, as they develop severe hyperglycemia due to the absence of mature pancreatic β-cells. Pax4 also directly regulates the expression of Arx, a gene that plays a crucial role in α-cell specification. Comparative analysis of Pax4 and Arx mutants, as well as Arx/Pax4 double mutants, showed that islet subtype destiny is mainly directed by cross-repression of the Pax4 and Arx factors. Importantly, the ectopic expression of Pax4 in α-cells was found sufficient to induce their neogenesis and conversion into β-like cells, not only during development but also in adult rodents. Therefore, differentiated endocrine α-cells can be considered as a putative source for insulin-producing β-like cells. These findings have clearly widened our understanding regarding pancreatic development, but they also open new research avenues in the context of diabetes research.