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Publication

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

Authors	Yang YP, Magnuson MA, Stein R, Wright CV
Submitted By	Submitted Externally on 5/5/2017
Status	Published
Journal	Development (Cambridge, England)
Year	2017
Date Published
Volume : Pages	144 : 248 - 257
PubMed Reference	27993987
Abstract	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 ß cells in vivo Pdx1(?AREAII/-) 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(+) a relative to insulin(+) ß cells, associated with the transcriptional and epigenetic derepression of the a-cell-determining Arx gene in endocrine progenitors. There were also glucagon and insulin co-expressing cells, and ß cells that were incapable of maturation. Creating the Pdx1(?AREAII) state after cells entered an insulin-expressing stage led to immature and dysfunctional islet ß cells carrying abnormal chromatin marking in vital ß-cell-associated genes. Therefore, trans-regulatory integration through Area II mediates a surprisingly extensive range of progenitor and ß-cell-specific Pdx1 functions.

Genes

Symbol	Description
Pdx1	pancreatic and duodenal homeobox 1

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