Department of Molecular Biology and the Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
Department of Medicine and Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
PLoS Biol. 2019 Jul 19;17(7):e3000382. doi: 10.1371/journal.pbio.3000382. eCollection 2019 Jul.
The Hippo pathway directs cell differentiation during organogenesis, in part by restricting proliferation. How Hippo signaling maintains a proliferation-differentiation balance in developing tissues via distinct molecular targets is only beginning to be understood. Our study makes the unexpected finding that Hippo suppresses nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) signaling in pancreatic progenitors to permit cell differentiation and epithelial morphogenesis. We find that pancreas-specific deletion of the large tumor suppressor kinases 1 and 2 (Lats1/2PanKO) from mouse progenitor epithelia results in failure to differentiate key pancreatic lineages: acinar, ductal, and endocrine. We carried out an unbiased transcriptome analysis to query differentiation defects in Lats1/2PanKO. This analysis revealed increased expression of NFκB activators, including the pantetheinase vanin1 (Vnn1). Using in vivo and ex vivo studies, we show that VNN1 activates a detrimental cascade of processes in Lats1/2PanKO epithelium, including (1) NFκB activation and (2) aberrant initiation of epithelial-mesenchymal transition (EMT), which together disrupt normal differentiation. We show that exogenous stimulation of VNN1 or NFκB can trigger this cascade in wild-type (WT) pancreatic progenitors. These findings reveal an unexpected requirement for active suppression of NFκB by LATS1/2 during pancreas development, which restrains a cell-autonomous deleterious transcriptional program and thereby allows epithelial differentiation.
Hippo 通路在器官发生过程中指导细胞分化，部分通过限制增殖来实现。Hippo 信号通路如何通过不同的分子靶点在发育组织中维持增殖-分化平衡，这才刚刚开始被理解。我们的研究有一个出人意料的发现，即 Hippo 抑制胰腺祖细胞中的核因子 kappa 轻链增强子的活化 B 细胞（NFκB）信号，从而允许细胞分化和上皮形态发生。我们发现，小鼠祖细胞上皮中特异性敲除大肿瘤抑制激酶 1 和 2（Lats1/2PanKO）会导致关键胰腺谱系（腺泡、导管和内分泌）无法分化。我们进行了一项无偏转录组分析，以研究 Lats1/2PanKO 中的分化缺陷。该分析揭示了 NFκB 激活剂的表达增加，包括泛肽酶 vanin1（Vnn1）。通过体内和体外研究，我们表明 VNN1 在 Lats1/2PanKO 上皮中激活了一系列有害的过程，包括（1）NFκB 激活和（2）上皮-间充质转化（EMT）的异常起始，这两者共同破坏了正常的分化。我们表明，外源性刺激 VNN1 或 NFκB 可以在野生型（WT）胰腺祖细胞中触发这一级联反应。这些发现揭示了在胰腺发育过程中，LATS1/2 对 NFκB 的积极抑制的意外需求，这限制了自主的有害转录程序，从而允许上皮分化。
