- Yang YP, Magnuson MA, Stein R, Wright CV. The mammal-specific Pdx1 Area II enhancer has multiple essential functions in early endocrine-cell specification and postnatal β-cell maturation. Development (Cambridge, England). 2016 Dec 19. PMID: 27993987 [PubMed].
Much evidence supports the idea that the Pdx1 transcription factor is required for multiple aspects of pancreatic organogenesis, including early growth of the entire pancreatic epithelium, islet β-cell lineage allocation, and maintenance of fate and function in adult β cells. It remains unclear, however, to what extent Pdx1 expression and function depend upon trans-activation focused through 5' upstream conserved cis-regulatory regions and, in particular, if the mammal-specific Area II (located at -2139 to -1958 bp) affects minor or major aspects of organogenesis. We show that Area II is a primary effector of endocrine-selective transcription in epithelial multipotent cells, nascent endocrine progenitors, and differentiating and mature β cells in vivo Pdx1(ΔAREAII/NULL) mice exhibited a massive reduction in endocrine progenitor cells and progeny hormone-producing cells, indicating Area II activity as fundamental to mounting an effective endocrine lineage-specification program within the multipotent cell population. Moreover, creating an Area II-deleted state within already-specified Neurog3-expressing endocrine-progenitor cells increased the proportion of glucagon(+) α relative to insulin(+)β cells, associated with the transcriptional and epigenetic derepression of the α-cell-determining Arx gene in endocrine progenitors. There were also glucagon/insulin coexpressing cells, and β cells that were incapable of maturation. Creating the Pdx1(ΔAREAII) state after cells entered an insulin-expressing stage also led to immature and dysfunctional islet β cells carrying abnormal chromatin marking in vital β-cell-associated genes. Therefore, trans-regulatory integration through the mammal-restricted Area II mediates a surprisingly extensive range of progenitor and β-cell-specific functions of the Pdx1 gene.