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

Autor: Mathie Tenenbaum, Amar Abderrahmani, Amélie Bonnefond, Stéphane Dalle, Julien Bourry, Valery Gmyr, Philippe Froguel, Valérie Pawlowski, Nicole Beeler, Valérie Plaisance, Raphael Boutry, Hélène Ezanno, Clara Sanchez-Parra, Cécile Jacovetti, Romano Regazzi, Gianni Pasquetti, François Pattou, Syu-Ichi Hirai, Julie Kerr-Conte
Přispěvatelé: Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Institut d’Électronique, de Microélectronique et de Nanotechnologie - UMR 8520 (IEMN), Centrale Lille-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université Polytechnique Hauts-de-France (UPHF)-JUNIA (JUNIA), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), NanoBioInterfaces - IEMN (NBI - IEMN), Université catholique de Lille (UCL)-Université catholique de Lille (UCL)-Centrale Lille-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université Polytechnique Hauts-de-France (UPHF)-JUNIA (JUNIA), Université de Lausanne = University of Lausanne (UNIL), Recherche translationnelle sur le diabète - U 1190 (RTD), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Wakayama University, Imperial College London, 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., ANR-10-LABX-0046,EGID,EGID Diabetes Pole(2010), European Project: 294785,EC:FP7:ERC,ERC-2011-ADG_20110310,GEPIDIAB(2012), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Université de Lausanne (UNIL), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)
Jazyk: angličtina
Rok vydání: 2021
Předmět:
MAPK/ERK pathway
endocrine system
Biology
Mapk
Beta-cell mass
Transcriptome
Rats
Sprague-Dawley
03 medical and health sciences
Cellular and Molecular Neuroscience
Mice
[SPI]Engineering Sciences [physics]
Mitogen-Activated Protein Kinase 10
Pregnancy
Insulin-Secreting Cells
Animals
Cell Proliferation/drug effects
Cyclin D1/genetics
Cyclin D1/metabolism
Cyclin D2/genetics
Cyclin D2/metabolism
Female
Glucose/pharmacology
Humans
Insulin/metabolism
Insulin-Secreting Cells/cytology
Insulin-Secreting Cells/metabolism
MAP Kinase Kinase Kinases/antagonists & inhibitors
MAP Kinase Kinase Kinases/genetics
MAP Kinase Kinase Kinases/metabolism
Mice
Inbred C57BL
Mitogen-Activated Protein Kinase 10/antagonists & inhibitors
Mitogen-Activated Protein Kinase 10/genetics
Mitogen-Activated Protein Kinase 10/metabolism
Obesity/metabolism
Obesity/pathology
Pancreas/growth & development
Pancreas/metabolism
RNA Interference
RNA
Small Interfering/metabolism
Rats
Signal Transduction/drug effects
Obesity
Postnatal development
Gene silencing
Cyclin D2
Insulin
Cyclin D1
RNA
Small Interfering
Molecular Biology
Pancreas
Cyclin
Cell Proliferation
Pharmacology
Serine/threonine-specific protein kinase
0303 health sciences
geography
geography.geographical_feature_category
Kinase
030302 biochemistry & molecular biology
Cell Biology
Islet
MAP Kinase Kinase Kinases
Cell biology
Glucose
Molecular Medicine
Signal transduction
Signal Transduction
Zdroj: Cellular and Molecular Life Sciences
Cellular and Molecular Life Sciences, 2021, 78 (1), pp.287-298. ⟨10.1007/s00018-020-03499-7⟩
Cellular and molecular life sciences, vol. 78, no. 1, pp. 287-298
Cellular and Molecular Life Sciences, Springer Verlag, 2021, 78 (1), pp.287-298. ⟨10.1007/s00018-020-03499-7⟩
ISSN: 1420-682X
1420-9071
Popis: International audience; 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 stimu- lates 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 fjnd that activation of Jnk3 signalling by Dlk could be a key mechanism for adapting islet beta-cell mass during postnatal development and weight gain.
Databáze: OpenAIRE
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