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The Map3k12 (Dlk)/JNK3 signaling pathway is required for pancreatic beta-cell proliferation during postnatal development

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Abstract

Unveiling the key pathways underlying postnatal beta-cell proliferation can be instrumental to decipher the mechanisms of beta-cell mass plasticity to increased physiological demand of insulin during weight gain and pregnancy. Using transcriptome and global Serine Threonine Kinase activity (STK) analyses of islets from newborn (10 days old) and adult rats, we found that highly proliferative neonatal rat islet cells display a substantially elevated activity of the mitogen activated protein 3 kinase 12, also called dual leucine zipper-bearing kinase (Dlk). As a key upstream component of the c-Jun amino terminal kinase (Jnk) pathway, Dlk overexpression was associated with increased Jnk3 activity and was mainly localized in the beta-cell cytoplasm. We provide the evidence that Dlk associates with and activates Jnk3, and that this cascade stimulates the expression of Ccnd1 and Ccnd2, two essential cyclins controlling postnatal beta-cell replication. Silencing of Dlk or of Jnk3 in neonatal islet cells dramatically hampered primary beta-cell replication and the expression of the two cyclins. Moreover, the expression of Dlk, Jnk3, Ccnd1 and Ccnd2 was induced in high replicative islet beta cells from ob/ob mice during weight gain, and from pregnant female rats. In human islets from non-diabetic obese individuals, DLK expression was also cytoplasmic and the rise of the mRNA level was associated with an increase of JNK3, CCND1 and CCND2 mRNA levels, when compared to islets from lean and obese patients with diabetes. In conclusion, we find that activation of Jnk3 signalling by Dlk could be a key mechanism for adapting islet beta-cell mass during postnatal development and weight gain.

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Abbreviations

Ccnd:

Cyclin D

Cdk:

Cyclin-dependent kinase

Cdkn:

Cyclin-dependent kinase inhibitor

DLK:

Dual leucine Zipper Kinase

JNK:

C-Jun amino terminal kinase

MAP3K12:

Mitogen-activated protein kinase 12

MAPK10:

Mitogen-activated protein kinase 10

STK:

Serine threonine kinase

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Acknowledgements

We would like to thank Mrs Laure Rolland for the technical assistance and, Antonino Bongiovanni and Meryem Tardivel from the BICeL-Campus HU Facility for access to systems and technical advice.

Funding

This work was supported by grants from “Société Francophone du Diabète (SFD)”, “European Genomic Institute for Diabetes” (E.G.I.D., ANR-10-LABEX-46) and European Commission, European Research Council (GEPIDIAB 294785 to P.F.), and by a grant from the Swiss National Science Foundation (310030-169480 to RR). Human islets were provided by the European Consortium for Islet Transplantation, funded by the Juvenile Diabetes Research Foundation International.

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Authors and Affiliations

  1. Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8199-EGID, 59000, Lille, France

    Mathie Tenenbaum, Valérie Plaisance, Raphael Boutry, Valérie Pawlowski, Hélène Ezanno, Julien Bourry, Nicole Beeler, Amélie Bonnefond, Philippe Froguel & Amar Abderrahmani

  2. Univ. Lille, CNRS, Centrale Lille, ISEN, Univ. Valenciennes, UMR 8520, IEMN, 59000, Lille, France

    Valérie Plaisance, Valérie Pawlowski & Amar Abderrahmani

  3. Department of Fundamental Neuroscience, University of Lausanne, Lausanne, Switzerland

    Cécile Jacovetti, Clara Sanchez-Parra & Romano Regazzi

  4. Univ. Lille, Inserm, CHU Lille, U1190-EGID, 59000, Lille, France

    Gianni Pasquetti, Valery Gmyr, Julie Kerr-Conte & François Pattou

  5. Institut de Génomique Fonctionnelle, CNRS UMR5203, INSERM U1191, Montpellier University, Montpellier, France

    Stéphane Dalle

  6. Départment of Biology, Wakayama University, Wakayama, Japan

    Syu-ichi Hirai

  7. Department of Medicine, Section of Genomics of Common Disease, Imperial College London, London, UK

    Amélie Bonnefond, Philippe Froguel & Amar Abderrahmani

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  1. Mathie Tenenbaum
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Contributions

MT, JKC, FP, RR, AB, PF and AA contributed to the study design and interpretation of the data. MT, SD, AB, PF and AA wrote and edited the manuscript. MT, VPL, VP, CSP, HE, RB, VG, CJ, JB, NB, GP performed the experiments and analysed the data. All authors read and approved the submission of the manuscript.

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Correspondence to Mathie Tenenbaum or Amar Abderrahmani.

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Tenenbaum, M., Plaisance, V., Boutry, R. et al. The Map3k12 (Dlk)/JNK3 signaling pathway is required for pancreatic beta-cell proliferation during postnatal development. Cell. Mol. Life Sci. 78, 287–298 (2021). https://doi.org/10.1007/s00018-020-03499-7

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