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dc.contributor.authorDuan, S.
dc.contributor.authorSawyer, T.W.
dc.contributor.authorSontz, R.A.
dc.contributor.authorWieland, B.A.
dc.contributor.authorDiaz, A.F.
dc.contributor.authorMerchant, J.L.
dc.date.accessioned2022-11-18T22:13:12Z
dc.date.available2022-11-18T22:13:12Z
dc.date.issued2022
dc.identifier.citationDuan, S., Sawyer, T. W., Sontz, R. A., Wieland, B. A., Diaz, A. F., & Merchant, J. L. (2022). GFAP-directed Inactivation of Men1 Exploits Glial Cell Plasticity in Favor of Neuroendocrine Reprogramming. Cellular and Molecular Gastroenterology and Hepatology, 14(5), 1025–1051.
dc.identifier.issn2352-345X
dc.identifier.pmid35835391
dc.identifier.doi10.1016/j.jcmgh.2022.06.009
dc.identifier.urihttp://hdl.handle.net/10150/666872
dc.description.abstractBackground & Aims: Efforts to characterize the signaling mechanisms that underlie gastroenteropancreatic neoplasms (GEP-NENs) are precluded by a lack of comprehensive models that recapitulate pathogenesis. Investigation into a potential cell-of-origin for gastrin-secreting NENs revealed a non-cell autonomous role for loss of menin in neuroendocrine cell specification, resulting in an induction of gastrin in enteric glia. Here, we investigated the hypothesis that cell autonomous Men1 inactivation in glial fibrillary acidic protein (GFAP)-expressing cells induced neuroendocrine differentiation and tumorigenesis. Methods: Transgenic GFAPΔMen1 mice were generated by conditional GFAP-directed Men1 deletion in GFAP-expressing cells. Cre specificity was confirmed using a tdTomato reporter. GFAPΔMen1 mice were evaluated for GEP-NEN development and neuroendocrine cell hyperplasia. Small interfering RNA-mediated Men1 silencing in a rat enteric glial cell line was performed in parallel. Results: GFAPΔMen1 mice developed pancreatic NENs, in addition to pituitary prolactinomas that phenocopied the human MEN1 syndrome. GFAPΔMen1 mice exhibited gastric neuroendocrine hyperplasia that coincided with a significant loss of GFAP expression. Men1 deletion induced loss of glial-restricted progenitor lineage markers and an increase in neuroendocrine genes, suggesting a reprogramming of GFAP+ cells. Deleting Kif3a, a mediator of Hedgehog signaling, in GFAP-expressing cells attenuated neuroendocrine hyperplasia by restricting the neuroendocrine cell fate. Similar results in the pancreas were observed when Sox10 was used to delete Men1. Conclusions: GFAP-directed Men1 inactivation exploits glial cell plasticity in favor of neuroendocrine differentiation. © 2022 The Authors
dc.language.isoen
dc.publisherElsevier Inc.
dc.rightsCopyright © 2022 The Authors. Published by Elsevier Inc. on behalf of the AGA Institute. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0
dc.subjectEnteric Glia
dc.subjectGastrinomas
dc.subjectHedgehog Signaling
dc.subjectKIF3A
dc.subjectPrimary Cilia
dc.subjectSOX10
dc.titleGFAP-directed Inactivation of Men1 Exploits Glial Cell Plasticity in Favor of Neuroendocrine Reprogramming
dc.typeArticle
dc.typetext
dc.contributor.departmentUniversity of Arizona College of Medicine, Department of Medicine, Division of Gastroenterology
dc.contributor.departmentWyant College of Optical Sciences, University of Arizona
dc.identifier.journalCellular and Molecular Gastroenterology and Hepatology
dc.description.noteOpen access journal
dc.description.collectioninformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.
dc.eprint.versionFinal published version
dc.source.journaltitleCellular and Molecular Gastroenterology and Hepatology
refterms.dateFOA2022-11-18T22:13:12Z


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Copyright © 2022 The Authors. Published by Elsevier Inc. on behalf of the AGA Institute. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Except where otherwise noted, this item's license is described as Copyright © 2022 The Authors. Published by Elsevier Inc. on behalf of the AGA Institute. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).