Abstract
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.
Highlights
Hippo is a major regulator of the critical balance between progenitor cell renewal, proliferation, and differentiation during embryogenesis [1]
In WT pancreatic epithelium, pLATS1 and pLATS2 proteins were expressed at the phosphatase receptor type C; pYAP1, phosphoyes-associated protein 1; qPCR, quantitative polymerase chain reaction; RELA, RELA protooncogene, NF-KB subunit; RNA-seq, RNA sequencing; ROS, reactive oxygen species; RT, room temperature; SNAI2, snail2; sex-determining region Y-box 9 protein (SOX9), sex determining region Y-box 9 protein; TAZ, transcriptional coactivator with PDZ-binding motif; TEAD, TEA domain transcription factor; TF, transcription factor; tmx, tamoxifen; TSS, transcription start site; VIM, vimentin; VNN1, vanin1; WT, wild type; WWTR1, WW domain containing transcription regulator 1; YAP1, yesassociated protein 1; zinc finger E-box binding homeobox 1 (ZEB1), zinc finger Ebox binding homeobox 1
We show a critical requirement for active restriction of YAP1/TAZ and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) pathways in pancreas to allow lineage differentiation and morphogenesis (Fig 7)
Summary
Hippo is a major regulator of the critical balance between progenitor cell renewal, proliferation, and differentiation during embryogenesis [1]. The Hippo pathway consists of a kinase cascade, including the upstream serine/threonine kinases 4 and 3 (or mammalian STE20-like protein kinases 1 and 2 [MST1/2]) [2, 3]. LATS1/2 constrain NFκB to permit pancreatic progenitor differentiation and from the Hamon Center for Regenerative Science and Medicine (utsouthwestern.edu/ research/regenerative) to OC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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