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

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.

journal_name

PLoS Biol

journal_title

PLoS biology

authors

Braitsch CM,Azizoglu DB,Htike Y,Barlow HR,Schnell U,Chaney CP,Carroll TJ,Stanger BZ,Cleaver O

doi

10.1371/journal.pbio.3000382

subject

Has Abstract

pub_date

2019-07-19 00:00:00

pages

e3000382

issue

7

eissn

1544-9173

issn

1545-7885

pii

PBIOLOGY-D-18-01109

journal_volume

17

pub_type

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