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The FOXP1, FOXP2 and FOXP4 transcription factors are required for islet alpha cell proliferation and function in mice

MPS-Authors
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Fisher,  Simon E.
Language and Genetics Department, MPI for Psycholinguistics, Max Planck Society;
Donders Institute for Brain, Cognition and Behaviour, External Organizations;

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Fulltext (public)

Spaeth_etal_diabetologia_2015.pdf
(Publisher version), 5MB

Supplementary Material (public)

125_2015_3635_MOESM1_ESM.pdf
(Supplementary material), 598KB

125_2015_3635_MOESM2_ESM.pdf
(Supplementary material), 637KB

125_2015_3635_MOESM3_ESM.pdf
(Supplementary material), 740KB

125_2015_3635_MOESM4_ESM.pdf
(Supplementary material), 896KB

125_2015_3635_MOESM5_ESM.pdf
(Supplementary material), 698KB

125_2015_3635_MOESM6_ESM.pdf
(Supplementary material), 474KB

125_2015_3635_MOESM7_ESM.pdf
(Supplementary material), 759KB

125_2015_3635_MOESM8_ESM-1.pdf
(Supplementary material), 791KB

Citation

Spaeth, J. M., Hunter, C. S., Bonatakis, L., Guo, M., French, C. A., Slack, I., et al. (2015). The FOXP1, FOXP2 and FOXP4 transcription factors are required for islet alpha cell proliferation and function in mice. Diabetologia, 58, 1836-1844. doi:10.1007/s00125-015-3635-3.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0027-9D94-C
Abstract
Aims/hypothesis Several forkhead box (FOX) transcription factor family members have important roles in controlling pancreatic cell fates and maintaining beta cell mass and function, including FOXA1, FOXA2 and FOXM1. In this study we have examined the importance of FOXP1, FOXP2 and FOXP4 of the FOXP subfamily in islet cell development and function. Methods Mice harbouring floxed alleles for Foxp1, Foxp2 and Foxp4 were crossed with pan-endocrine Pax6-Cre transgenic mice to generate single and compound Foxp mutant mice. Mice were monitored for changes in glucose tolerance by IPGTT, serum insulin and glucagon levels by radioimmunoassay, and endocrine cell development and proliferation by immunohistochemistry. Gene expression and glucose-stimulated hormone secretion experiments were performed with isolated islets. Results Only the triple-compound Foxp1/2/4 conditional knockout (cKO) mutant had an overt islet phenotype, manifested physiologically by hypoglycaemia and hypoglucagonaemia. This resulted from the reduction in glucagon-secreting alpha cell mass and function. The proliferation of alpha cells was profoundly reduced in Foxp1/2/4 cKO islets through the effects on mediators of replication (i.e. decreased Ccna2, Ccnb1 and Ccnd2 activators, and increased Cdkn1a inhibitor). Adult islet Foxp1/2/4 cKO beta cells secrete insulin normally while the remaining alpha cells have impaired glucagon secretion. Conclusions/interpretation Collectively, these findings reveal an important role for the FOXP1, 2, and 4 proteins in governing postnatal alpha cell expansion and function.