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Insertional Mutagenesis Identifies a STAT3/Arid1b/?-catenin Pathway Driving Neurofibroma Initiation.

ABSTRACT: To identify genes and signaling pathways that initiate Neurofibromatosis type 1 (NF1) neurofibromas, we used unbiased insertional mutagenesis screening, mouse models, and molecular analyses. We mapped an Nf1-Stat3-Arid1b/?-catenin pathway that becomes active in the context of Nf1 loss. Genetic deletion of Stat3 in Schwann cell progenitors (SCPs) and Schwann cells (SCs) prevents neurofibroma formation, decreasing SCP self-renewal and ?-catenin activity. ?-catenin expression rescues effects of Stat3 loss in SCPs. Importantly, P-STAT3 and ?-catenin expression correlate in human neurofibromas. Mechanistically, P-Stat3 represses Gsk3? and the SWI/SNF gene Arid1b to increase ?-catenin. Knockdown of Arid1b or Gsk3? in Stat3(fl/fl);Nf1(fl/fl);DhhCre SCPs rescues neurofibroma formation after in vivo transplantation. Stat3 represses Arid1b through histone modification in a Brg1-dependent manner, indicating that epigenetic modification plays a role in early tumorigenesis. Our data map a neural tumorigenesis pathway and support testing JAK/STAT and Wnt/?-catenin pathway inhibitors in neurofibroma therapeutic trials.

SUBMITTER: Wu J 

PROVIDER: S-EPMC4782770 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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To identify genes and signaling pathways that initiate Neurofibromatosis type 1 (NF1) neurofibromas, we used unbiased insertional mutagenesis screening, mouse models, and molecular analyses. We mapped an Nf1-Stat3-Arid1b/β-catenin pathway that becomes active in the context of Nf1 loss. Genetic deletion of Stat3 in Schwann cell progenitors (SCPs) and Schwann cells (SCs) prevents neurofibroma formation, decreasing SCP self-renewal and β-catenin activity. β-catenin expression rescues effects of Sta  ...[more]

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