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

• Published in: Cellular and molecular life sciences : CMLS Vol. 78; no. 1; pp. 287 - 298
• Main Authors: Tenenbaum, Mathie, Plaisance, Valérie, Boutry, Raphael, Pawlowski, Valérie, Jacovetti, Cécile, Sanchez-Parra, Clara, Ezanno, Hélène, Bourry, Julien, Beeler, Nicole, Pasquetti, Gianni, Gmyr, Valery, Dalle, Stéphane, Kerr-Conte, Julie, Pattou, François, Hirai, Syu-ichi, Regazzi, Romano, Bonnefond, Amélie, Froguel, Philippe, Abderrahmani, Amar
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.01.2021; Springer Nature B.V; Springer Verlag
• Subjects: Animal models; Animals; Beta cells; Biochemistry; Biomedical and Life Sciences; Biomedicine; Cell Biology; Cell growth; Cell proliferation; Cell Proliferation - drug effects; Cyclin D1 - genetics; Cyclin D1 - metabolism; Cyclin D2 - genetics; Cyclin D2 - metabolism; Cyclins; Cytoplasm; Diabetes mellitus; Engineering Sciences; Female; Gene expression; Glucose - pharmacology; Humans; Insulin; Insulin - metabolism; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - metabolism; Islet cells; JNK3 protein; Kinases; Leucine; Leucine zipper proteins; Life Sciences; MAP Kinase Kinase Kinases - antagonists & inhibitors; MAP Kinase Kinase Kinases - genetics; MAP Kinase Kinase Kinases - metabolism; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase 10 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 10 - genetics; Mitogen-Activated Protein Kinase 10 - metabolism; Neonates; Obesity - metabolism; Obesity - pathology; Original; Original Article; Pancreas; Pancreas - growth & development; Pancreas - metabolism; Protein-serine/threonine kinase; Rats; Rats, Sprague-Dawley; Replication; RNA Interference; RNA, Small Interfering - metabolism; Signal transduction; Signal Transduction - drug effects; Signaling; Transcription factors; Transcriptomes; Weight; Pregnancy; Obesity; Beta-cell mass; Mapk; Postnatal development
• DOI: 10.1007/s00018-020-03499-7
• ISSN: 1420-682X

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.