The Role of ARX in Pancreatic Endocrine Specificatin of hESCs.

NGN3 induction in hESC derived pancreatic progenitors (PDX+ NKX6.1+) initiates the endocrine lineage. (A) In wild type hESCs, pancreatic endocrine progenitors express both PAX4 and ARX that are mutually corepressive. High expression of ARX specifies and maintains glucagon positive cells while elevated PAX4 levels drives the insulin and somatostatin lineages in normal abundance. (B) In the absence of functional ARX (ARX ko), repression of PAX4 is disrupted leading to a bias toward the insulin/somatostatin lineage. Elevated expression of HHEX as well as altered expression of other transcription factors, leads to large numbers of somatostatin cells at the expense of both insulin and glucagon lineages. (C) Re-expression of ARX in ARX ko pancreatic progenitors temporarily rescues ARX expression resulting in recovery of PAX6 expression (and other factors) which restores the specification of insulin positive cells. Glucagon positive cells are not rescued due to poorly sustained ARX expression in subsequent endocrine cells.