The mammal-specific Pdx1 Area II enhancer has multiple essential functions in early endocrine cell specification and postnatal β-cell maturation.

Yang YP, Magnuson MA, Stein R, Wright CV
Development. 2017 144 (2): 248-257

PMID: 27993987 · PMCID: PMC5394757 · DOI:10.1242/dev.143123

The transcription factor Pdx1 is required for multiple aspects of pancreatic organogenesis. It remains unclear to what extent Pdx1 expression and function depend upon trans-activation through 5' conserved cis-regulatory regions and, in particular, whether the mammal-specific Area II (-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 mice exhibit a massive reduction in endocrine progenitor cells and progeny hormone-producing cells, indicating that Area II activity is fundamental to mounting an effective endocrine lineage-specification program within the multipotent cell population. 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 and insulin co-expressing cells, and β cells that were incapable of maturation. Creating the Pdx1 state after cells entered an insulin-expressing stage led to immature and dysfunctional islet β cells carrying abnormal chromatin marking in vital β-cell-associated genes. Therefore, trans-regulatory integration through Area II mediates a surprisingly extensive range of progenitor and β-cell-specific Pdx1 functions.

© 2017. Published by The Company of Biologists Ltd.

MeSH Terms (15)

Animals Binding Sites Cell Differentiation Embryo, Mammalian Enhancer Elements, Genetic Gene Expression Regulation, Developmental Homeodomain Proteins Insulin-Secreting Cells Islets of Langerhans Mammals Mice Mice, Transgenic Organogenesis Species Specificity Trans-Activators

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