LATS1/2 suppress NFκB and aberrant EMT initiation to permit pancreatic progenitor differentiation

Caitlin M. Braitsch, D. Berfin Azizoglu, Yadanar Htike, Haley R. Barlow, Ulrike Schnell, Christopher P. Chaney, Thomas J Carroll, Ben Z. Stanger, Ondine Cleaver

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere3000382
JournalPLoS biology
Volume17
Issue number7
DOIs
StatePublished - Jul 1 2019

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ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Braitsch, C. M., Azizoglu, D. B., Htike, Y., Barlow, H. R., Schnell, U., Chaney, C. P., Carroll, T. J., Stanger, B. Z., & Cleaver, O. (2019). LATS1/2 suppress NFκB and aberrant EMT initiation to permit pancreatic progenitor differentiation. PLoS biology, 17(7), [e3000382]. https://doi.org/10.1371/journal.pbio.3000382