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The transcription factor Pax6 is required for pancreatic β cell identity, glucose-regulated ATP synthesis and Ca2+ dynamics in adult mice.

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Title: The transcription factor Pax6 is required for pancreatic β cell identity, glucose-regulated ATP synthesis and Ca2+ dynamics in adult mice.
Authors: Mitchell, RK
Nguyen-Tu, MS
Chabosseau, P
Callingham, RM
Pullen, TJ
Cheung, R
Leclerc, I
Hodson, DJ
Rutter, GA
Item Type: Journal Article
Abstract: Heterozygous mutations in the human paired box gene PAX6 lead to impaired glucose tolerance. Although embryonic deletion of the Pax6 gene in mice leads to the loss of most pancreatic islet cell types, the functional consequences of Pax6 loss in adults are poorly defined. Here, we developed a mouse line in which Pax6 was selectively inactivated in β cells by crossing animals with floxed Pax6 alleles to mice expressing the inducible Pdx1CreERT transgene. Pax6 deficiency, achieved by tamoxifen injection, caused progressive hyperglycemia. While β-cell mass was preserved 8 days post injection, total insulin content and insulin:chromogranin A immunoreactivity were reduced by ~60%, and glucose-stimulated insulin secretion was eliminated. RNAseq and qRT-PCR analyses revealed that whereas the expression of key β cell genes including Ins2, Slc30a8, MafA, Slc2a2, G6pc2 and Glp1r was reduced after Pax6 deletion, that of several genes which are usually selectively repressed ("disallowed") in β-cells, including Slc16a1, was increased. Assessed in intact islets, glucose-induced ATP:ADP increases were significantly reduced (p<0.05) in βPax6KO versus control β cells, and the former displayed attenuated increases in cytosolic Ca2+. Unexpectedly, glucose-induced increases in intercellular connectivity were enhanced after Pax6 deletion, consistent with increases in the expression of the glucose sensor glucokinase, but decreases in that of two transcription factors usually expressed in fully differentiated β-cells, Pdx1 and Nkx6.1, as observed in islet "hub" cells. These results indicate that Pax6 is required for the functional identity of adult β cells. Furthermore, deficiencies in β cell glucose-sensing are likely to contribute to defective insulin secretion in human carriers of PAX6 mutations.
Issue Date: 4-Apr-2017
Date of Acceptance: 3-Apr-2017
URI: http://hdl.handle.net/10044/1/49152
DOI: https://dx.doi.org/10.1074/jbc.M117.784629
ISSN: 1083-351X
Publisher: American Society for Biochemistry and Molecular Biology
Start Page: 8892
End Page: 8906
Journal / Book Title: Journal of Biological Chemistry
Volume: 292
Issue: 21
Copyright Statement: © 2017 by The American Society for Biochemistry and Molecular Biology, Inc. Final version free via Creative Commons CC-BY license (https://creativecommons.org/licenses/by/4.0/).
Sponsor/Funder: Medical Research Council (MRC)
Wellcome Trust
Diabetes UK
Diabetes UK
Funder's Grant Number: MR/K001981/1
098424/Z/12/ZR
15821
15 / 0005275
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
calcium
diabetes
gene expression
imaging
islet
insulin
INDUCED INSULIN-SECRETION
GLUCAGON-SECRETION
BLOOD-GLUCOSE
ALPHA-CELLS
EARLY-ONSET
ISLETS
EXPRESSION
GENES
HORMONE
REVEALS
Adenosine Triphosphate
Animals
Calcium
Calcium Signaling
Gene Expression Regulation
Glucose
Humans
Insulin-Secreting Cells
Mice
Mice, Knockout
PAX6 Transcription Factor
06 Biological Sciences
11 Medical And Health Sciences
03 Chemical Sciences
Publication Status: Published
Conference Place: United States
Appears in Collections:Department of Medicine
Faculty of Medicine



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