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

Fingerprint

Cell signaling
Epithelial-Mesenchymal Transition
pancreas
cell differentiation
Tumors
Cell Differentiation
Pancreas
Phosphotransferases
epithelium
Epithelium
Chemical activation
Tissue
Defects
Organogenesis
Gene Expression Profiling
in vivo studies
organogenesis
transcriptomics
Morphogenesis
B-lymphocytes

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., ... 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

LATS1/2 suppress NFκB and aberrant EMT initiation to permit pancreatic progenitor differentiation. / Braitsch, Caitlin M.; Azizoglu, D. Berfin; Htike, Yadanar; Barlow, Haley R.; Schnell, Ulrike; Chaney, Christopher P.; Carroll, Thomas J; Stanger, Ben Z.; Cleaver, Ondine.

In: PLoS biology, Vol. 17, No. 7, e3000382, 01.07.2019.

Research output: Contribution to journalArticle

Braitsch, CM, Azizoglu, DB, Htike, Y, Barlow, HR, Schnell, U, Chaney, CP, Carroll, TJ, Stanger, BZ & Cleaver, O 2019, 'LATS1/2 suppress NFκB and aberrant EMT initiation to permit pancreatic progenitor differentiation', PLoS biology, vol. 17, no. 7, e3000382. https://doi.org/10.1371/journal.pbio.3000382
Braitsch CM, Azizoglu DB, Htike Y, Barlow HR, Schnell U, Chaney CP et al. LATS1/2 suppress NFκB and aberrant EMT initiation to permit pancreatic progenitor differentiation. PLoS biology. 2019 Jul 1;17(7). e3000382. https://doi.org/10.1371/journal.pbio.3000382
Braitsch, Caitlin M. ; Azizoglu, D. Berfin ; Htike, Yadanar ; Barlow, Haley R. ; Schnell, Ulrike ; Chaney, Christopher P. ; Carroll, Thomas J ; Stanger, Ben Z. ; Cleaver, Ondine. / LATS1/2 suppress NFκB and aberrant EMT initiation to permit pancreatic progenitor differentiation. In: PLoS biology. 2019 ; Vol. 17, No. 7.
@article{a5254dfe37a9441c9cc385f0d05cb8f3,
title = "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.",
author = "Braitsch, {Caitlin M.} and Azizoglu, {D. Berfin} and Yadanar Htike and Barlow, {Haley R.} and Ulrike Schnell and Chaney, {Christopher P.} and Carroll, {Thomas J} and Stanger, {Ben Z.} and Ondine Cleaver",
year = "2019",
month = "7",
day = "1",
doi = "10.1371/journal.pbio.3000382",
language = "English (US)",
volume = "17",
journal = "PLoS Biology",
issn = "1544-9173",
publisher = "Public Library of Science",
number = "7",

}

TY - JOUR

T1 - LATS1/2 suppress NFκB and aberrant EMT initiation to permit pancreatic progenitor differentiation

AU - Braitsch, Caitlin M.

AU - Azizoglu, D. Berfin

AU - Htike, Yadanar

AU - Barlow, Haley R.

AU - Schnell, Ulrike

AU - Chaney, Christopher P.

AU - Carroll, Thomas J

AU - Stanger, Ben Z.

AU - Cleaver, Ondine

PY - 2019/7/1

Y1 - 2019/7/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85070849870&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85070849870&partnerID=8YFLogxK

U2 - 10.1371/journal.pbio.3000382

DO - 10.1371/journal.pbio.3000382

M3 - Article

VL - 17

JO - PLoS Biology

JF - PLoS Biology

SN - 1544-9173

IS - 7

M1 - e3000382

ER -