Imperial College London
Alternate

DrTimothyPullen

Faculty of Medicine, Department of Metabolism, Digestion and Reproduction

Honorary Lecturer
 
 
 
//

Contact

 

t.pullen Website

 
 
//

Location

 

329ICTEM buildingHammersmith Campus

//

Summary

 

Publications

Citation

BibTex format

@article{Mitchell:2017:10.1074/jbc.M117.784629,
author = {Mitchell, RK and Nguyen-Tu, MS and Chabosseau, P and Callingham, RM and Pullen, TJ and Cheung, R and Leclerc, I and Hodson, DJ and Rutter, GA},
doi = {10.1074/jbc.M117.784629},
journal = {Journal of Biological Chemistry},
pages = {8892--8906},
title = {The transcription factor Pax6 is required for pancreatic β cell identity, glucose-regulated ATP synthesis and Ca2+ dynamics in adult mice.},
url = {http://dx.doi.org/10.1074/jbc.M117.784629},
volume = {292},
year = {2017}
}
Download

RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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.
AU  - Mitchell,RK
AU  - Nguyen-Tu,MS
AU  - Chabosseau,P
AU  - Callingham,RM
AU  - Pullen,TJ
AU  - Cheung,R
AU  - Leclerc,I
AU  - Hodson,DJ
AU  - Rutter,GA
DO  - 10.1074/jbc.M117.784629
EP  - 8906
PY  - 2017///
SN  - 1083-351X
SP  - 8892
TI  - The transcription factor Pax6 is required for pancreatic β cell identity, glucose-regulated ATP synthesis and Ca2+ dynamics in adult mice.
T2  - Journal of Biological Chemistry
UR  - http://dx.doi.org/10.1074/jbc.M117.784629
UR  - http://www.ncbi.nlm.nih.gov/pubmed/28377501
UR  - http://hdl.handle.net/10044/1/49152
VL  - 292
ER  -
Download