The concerted activities of Pax4 and Nkx2.2 are essential to initiate pancreatic β-cell differentiation

Pancreatic β cells play a central role in maintaining glucose homeostasis because they secrete insulin in response to increased level of blood glucose; failure of this capacity constitutes a major component of the pathogenesis of diabetes. The identification of key regulators of pancreatic β-cell differentiation is relevant for the overall understanding of this process and for future experiments aimed at regenerating insulin-producing β cells from pancreatic or embryonic stem cells. Several studies using transgenic or knockout mice have established that the development and function of pancreatic β cells are controlled by several genes encoding specific transcription factors. By inactivating the homeobox gene Pax4, we previously demonstrated that its function is required for the formation of mature insulin-producing cells. Here, we show that during pancreas ontogeny, Pax4 is expressed in differentiating endocrine cells, including β cells. Pax4 activity appears essential for appropriate initiation of β-cell differentiation because loss of Pax4 prevents the expression of Pdx1, HB9 and insulin in β-cell precursors. This role of Pax4 appears to be accomplished via its genetic interaction with another homeobox gene, Nkx2.2.