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Diabetologia
Published in: Diabetologia 10/2011

01-10-2011 | Article

The Krüppel-like zinc finger protein GLIS3 transactivates neurogenin 3 for proper fetal pancreatic islet differentiation in mice

Authors: Y. Yang, B. H-J. Chang, V. Yechoor, W. Chen, L. Li, M.-J. Tsai, L. Chan

Published in: Diabetologia | Issue 10/2011

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Abstract

Aims/hypothesis

Mutations in GLIS3, which encodes a Krüppel-like zinc finger transcription factor, were found to underlie sporadic neonatal diabetes. Inactivation of Glis3 by gene targeting in mice was previously shown to lead to neonatal diabetes, but the underlying mechanism remains largely unknown. We aimed to elucidate the mechanism of action of GLIS family zinc finger 3 (GLIS3) in Glis3 −/− mice and to further decipher its action in in-vitro systems.

Methods

We created Glis3 −/− mice and monitored the morphological and biochemical phenotype of their pancreatic islets at different stages of embryonic development. We combined these observations with experiments on Glis3 expressed in cultured cells, as well as in in vitro systems in the presence of other reconstituted components.

Results

In vivo and in vitro analyses placed Glis3 upstream of Neurog3, the endocrine pancreas lineage-defining transcription factor. We found that GLIS3 binds to specific GLIS3-response elements in the Neurog3 promoter, activating Neurog3 gene transcription both directly, and synergistically with hepatic nuclear factor 6 and forkhead box A2.

Conclusions/interpretation

These results indicate that GLIS3 controls fetal islet differentiation via direct transactivation of Neurog3, a perturbation that causes neonatal diabetes in mice.
Appendix
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Metadata
Title
The Krüppel-like zinc finger protein GLIS3 transactivates neurogenin 3 for proper fetal pancreatic islet differentiation in mice
Authors
Y. Yang
B. H-J. Chang
V. Yechoor
W. Chen
L. Li
M.-J. Tsai
L. Chan
Publication date
01-10-2011
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 10/2011
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-011-2255-9

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