Cellular and Molecular Life Sciences ( IF 8 ) Pub Date : 2020-03-18 , DOI: 10.1007/s00018-020-03499-7 Mathie Tenenbaum , Valérie Plaisance , Raphael Boutry , Valérie Pawlowski , Cécile Jacovetti , Clara Sanchez-Parra , Hélène Ezanno , Julien Bourry , Nicole Beeler , Gianni Pasquetti , Valery Gmyr , Stéphane Dalle , Julie Kerr-Conte , François Pattou , Syu-ichi Hirai , Romano Regazzi , Amélie Bonnefond , Philippe Froguel , Amar Abderrahmani
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.
中文翻译:
产后发育期间胰腺β细胞增殖需要Map3k12(Dlk)/ JNK3信号通路
摘要
揭示出生后β细胞增殖的关键途径可能有助于破译β细胞大量可塑性以增加体重和怀孕期间胰岛素的生理需求的机制。使用转录组和新生(10天大)和成年大鼠胰岛的全局丝氨酸苏氨酸激酶活性(STK)分析,我们发现高度增殖的新生大鼠胰岛细胞显示出促分裂素激活蛋白3激酶12(也称为“双亮氨酸拉链激酶(Dlk)。作为c-Jun氨基末端激酶(Jnk)途径的关键上游成分,Dlk过表达与Jnk3活性增加有关,并且主要位于β细胞质中。我们提供Dlk关联并激活Jnk3的证据,Ccnd1和Ccnd2,两个重要的细胞周期蛋白,控制出生后的β细胞复制。新生胰岛细胞中Dlk或Jnk3的沉默极大地阻碍了原代β细胞的复制和两个细胞周期蛋白的表达。此外,Dlk,Jnk3,Ccnd1和Ccnd2的表达在体重增加期间来自ob / ob小鼠和怀孕雌性大鼠的高复制性胰岛β细胞中被诱导。在非糖尿病性肥胖人群的人类胰岛中,DLK表达也呈细胞质,并且mRNA水平的升高与JNK3,CCND1和CCND2的升高有关与肥胖和肥胖糖尿病患者的胰岛相比,mRNA水平。总之,我们发现Dlk激活Jnk3信号传导可能是在产后发育和体重增加期间适应胰岛β细胞质量的关键机制。