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

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

  • Cell Mol Life Sci. 2021 Jan;78(1):287-298. doi: 10.1007/s00018-020-03499-7.
Mathie Tenenbaum 1,  Valérie Plaisance 2 3,  Raphael Boutry 2,  Valérie Pawlowski 2 3,  Cécile Jacovetti 4,  Clara Sanchez-Parra 4,  Hélène Ezanno 2,  Julien Bourry 2,  Nicole Beeler 2,  Gianni Pasquetti 5,  Valery Gmyr 5,  Stéphane Dalle 6,  Julie Kerr-Conte 5,  François Pattou 5,  Syu-Ichi Hirai 7,  Romano Regazzi 4,  Amélie Bonnefond 2 8,  Philippe Froguel 2 8,  Amar Abderrahmani 9 10 11
Affiliations

Affiliations

  • 1 Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8199-EGID, 59000, Lille, France. [email protected].
  • 2 Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8199-EGID, 59000, Lille, France.
  • 3 Univ. Lille, CNRS, Centrale Lille, ISEN, Univ. Valenciennes, UMR 8520, IEMN, 59000, Lille, France.
  • 4 Department of Fundamental Neuroscience, University of Lausanne, Lausanne, Switzerland.
  • 5 Univ. Lille, Inserm, CHU Lille, U1190-EGID, 59000, Lille, France.
  • 6 Institut de Génomique Fonctionnelle, CNRS UMR5203, INSERM U1191, Montpellier University, Montpellier, France.
  • 7 Départment of Biology, Wakayama University, Wakayama, Japan.
  • 8 Department of Medicine, Section of Genomics of Common Disease, Imperial College London, London, UK.
  • 9 Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8199-EGID, 59000, Lille, France. [email protected].
  • 10 Univ. Lille, CNRS, Centrale Lille, ISEN, Univ. Valenciennes, UMR 8520, IEMN, 59000, Lille, France. [email protected].
  • 11 Department of Medicine, Section of Genomics of Common Disease, Imperial College London, London, UK. [email protected].
PMID: 32189007 DOI: 10.1007/s00018-020-03499-7
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.

Keywords

Beta-cell mass; Mapk; Obesity; Postnatal development; Pregnancy.

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