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Diabetes. 2017 Nov;66(11):2830-2839. doi: 10.2337/db16-1516. Epub 2017 Jul 13.

Defining a Novel Role for the Pdx1 Transcription Factor in Islet β-Cell Maturation and Proliferation During Weaning.

Author information

1
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN.
2
Division of Endocrinology, Metabolism and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL.
3
Program in Developmental Biology, Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN.
4
Center for Stem Cell Biology, Vanderbilt University, Nashville, TN.
5
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN roland.stein@vanderbilt.edu.

Abstract

The transcription factor encoded by the Pdx1 gene is a critical transcriptional regulator, as it has fundamental actions in the formation of all pancreatic cell types, islet β-cell development, and adult islet β-cell function. Transgenic- and cell line-based experiments have identified 5'-flanking conserved sequences that control pancreatic and β-cell type-specific transcription, which are found within areas I (bp -2694 to -2561), II (bp -2139 to -1958), III (bp -1879 to -1799), and IV (bp -6200 to -5670). Because of the presence in area IV of binding sites for transcription factors associated with pancreas development and islet cell function, we analyzed how an endogenous deletion mutant affected Pdx1 expression embryonically and postnatally. The most striking result was observed in male Pdx1ΔIV mutant mice after 3 weeks of birth (i.e., the onset of weaning), with only a small effect on pancreas organogenesis and no deficiencies in their female counterparts. Compromised Pdx1 mRNA and protein levels in weaned male mutant β-cells were tightly linked with hyperglycemia, decreased β-cell proliferation, reduced β-cell area, and altered expression of Pdx1-bound genes that are important in β-cell replication, endoplasmic reticulum function, and mitochondrial activity. We discuss the impact of these novel findings to Pdx1 gene regulation and islet β-cell maturation postnatally.

PMID:
28705881
PMCID:
PMC5652607
[Available on 2018-11-01]
DOI:
10.2337/db16-1516
[Indexed for MEDLINE]
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