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  MiR-132 controls pancreatic beta cell proliferation and survival through Pten/Akt/Foxo3 signaling.

Mziaut, H., Henniger, G., Ganss, K., Hempel, S., Wolk, S., McChord, J., et al. (2020). MiR-132 controls pancreatic beta cell proliferation and survival through Pten/Akt/Foxo3 signaling. Molecular Metabolism, 31, 150-162. doi:10.1016/j.molmet.2019.11.012.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0005-8485-F Version Permalink: http://hdl.handle.net/21.11116/0000-0005-8489-B
Genre: Journal Article

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 Creators:
Mziaut, H., Author
Henniger, G., Author
Ganss, K., Author
Hempel, S., Author
Wolk, S., Author
McChord, J., Author
Chowdhury, K.1, Author              
Ravassard, P., Author
Knoch, K. P., Author
Krautz, C., Author
Weitz, J., Author
Grützmann, R., Author
Pilarsky, C., Author
Solimena, M., Author
Kersting, S., Author
Affiliations:
1Facility of Microarray Analyses, MPI for biophysical chemistry, Max Planck Society, ou_578589              

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Free keywords: miR-132; beta cell regeneration; Apoptosis; Pten/Akt/Foxo3a; Pancreatectomy
 Abstract: Objective: MicroRNAs (miRNAs) play an integral role in maintaining beta cell function and identity. Deciphering their targets and precise role, however, remains challenging. In this study, we aimed to identify miRNAs and their downstream targets involved in the regeneration of islet beta cells following partial pancreatectomy in mice. Methods: RNA from laser capture microdissected (LCM) islets of partially pancreatectomized and sham-operated mice were profiled with microarrays to identify putative miRNAs implicated in beta cell regeneration. Altered expression of the selected miRNAs, including miR-132, was verified by RT-PCR. Potential targets of miR-132 were selected through bioinformatic data mining. Predicted miR-132 targets were validated for their changed RNA, protein expression levels, and signaling upon miR-132 knockdown and/or overexpression in mouse MIN6 and human EndoC-beta H1 insulinoma cells. The ability of miR-132 to foster beta cell proliferation in vivo was further assessed in pancreatectomized miR-132(-/-) and control mice. Results: Partial pancreatectomy significantly increased the number of BrdU(+)/insulin(+) islet cells. Microarray profiling revealed that 14 miRNAs, including miR-132 and -141, were significantly upregulated in the LCM islets of the partially pancreatectomized mice compared to the LCM islets of the control mice. In the same comparison, miR-760 was the only downregulated miRNA. The changed expression of these miRNAs in the islets of the partially pancreatectomized mice was confirmed by RT-PCR only in the case of miR-132 and -141. Based on previous knowledge of its function, we focused our attention on miR-132. Downregulation of miR-132 reduced the proliferation of MIN6 cells while enhancing the levels of pro-apoptotic cleaved caspase-9. The opposite was observed in miR-132 overexpressing MIN6 cells. Microarray profiling, RT-PCR, and immunoblotting of the latter cells demonstrated their downregulated expression of Pten with concomitant increased levels of pro-proliferative factors phospho-Akt and phospho-Creb and inactivation of pro-apoptotic Foxo3a via its phosphorylation. Downregulation of Pten was further confirmed in the LCM islets of pancreatectomized mice compared to the sham-operated mice. Moreover, overexpression of miR-132 correlated with increased proliferation of EndoC-bH1 cells. The regeneration of beta cells following partial pancreatectomy was lower in the miR-132/212(-/-) mice than the control littermates. Conclusions: This study provides compelling evidence about the critical role of miR-132 for the regeneration of mouse islet beta cells through the downregulation of its target Pten. Hence, the miR-132/Pten/Akt/Foxo3 signaling pathway may represent a suitable target to enhance beta cell mass.

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Language(s): eng - English
 Dates: 2019-11-222020-01
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1016/j.molmet.2019.11.012
 Degree: -

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Title: Molecular Metabolism
Source Genre: Journal
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Pages: - Volume / Issue: 31 Sequence Number: - Start / End Page: 150 - 162 Identifier: -