The mammal-specific Pdx1 Area II enhancer has multiple essential functions in early endocrine-cell specification and postnatal {beta}-cell maturation [RESEARCH ARTICLE]

Yu-Ping Yang, Mark A. Magnuson, Roland Stein, and Christopher V.E. Wright

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^AREAII/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^AREAII 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.

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