The Map3k12 (Dlk)/JNK3 signaling pathway is required for pancreatic beta-cell proliferation during postnatal development
- 1 January 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cellular and Molecular Life Sciences
- Vol. 78 (1), 287-298
- https://doi.org/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,CCND1andCCND2 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.Funding Information
- Agence Nationale de la Recherche (ANR-10-LABEX-46)
This publication has 31 references indexed in Scilit:
- MicroRNAs contribute to compensatory β cell expansion during pregnancy and obesityJCI Insight, 2012
- Loss of DLK expression in WI-38 human diploid fibroblasts induces a senescent-like proliferation arrestBiochemical and Biophysical Research Communications, 2011
- Protein Kinases and Phosphatases in the Control of Cell FateEnzyme Research, 2011
- High Fat Diet Regulation of β-Cell Proliferation and β-Cell MassThe Open Endocrinology Journal, 2010
- FoxM1 Is Up-Regulated by Obesity and Stimulates β-Cell ProliferationMolecular Endocrinology, 2010
- Expansion of β-cell mass in response to pregnancyTrends in Endocrinology & Metabolism, 2010
- β-Cell Function in Obese-Hyperglycemic Mice [ob/ob Mice]Advances in Experimental Medicine and Biology, 2010
- Primary Graft Function, Metabolic Control, and Graft Survival After Islet TransplantationDiabetes Care, 2009
- The c-Jun N-Terminal Kinase Activator Dual Leucine Zipper Kinase Regulates Axon Growth and Neuronal Migration in the Developing Cerebral CortexJournal of Neuroscience, 2006
- Zonal Induction of Mixed Lineage Kinase ZPK/DLK/MUK Gene Expression in Regenerating Mouse LiverBiochemical and Biophysical Research Communications, 1998