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Development. 2017 Jan 15;144(2):248-257. doi: 10.1242/dev.143123. Epub 2016 Dec 19.

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

Author information

1
Vanderbilt University Program in Developmental Biology and Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232 USA.
2
Vanderbilt Center for Stem Cell Biology, Vanderbilt University, Nashville, TN 37232, USA.
3
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA.
4
Vanderbilt University Program in Developmental Biology and Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232 USA chris.wright@vanderbilt.edu.

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 β cells in vivo Pdx1ΔAREAII/- 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 Pdx1ΔAREAII 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.

KEYWORDS:

Cis-regulatory function; Lineage diversification; Mouse; Pancreatic endocrine progenitors; Pdx1 enhancer Area II

PMID:
27993987
PMCID:
PMC5394757
DOI:
10.1242/dev.143123
[Indexed for MEDLINE]
Free PMC Article

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