GFAP-directed Inactivation of Men1 Exploits Glial Cell Plasticity in Favor of Neuroendocrine Reprogramming

Suzann Duan, Travis W. Sawyer, Ricky A. Sontz, Bradley A. Wieland, Andres F. Diaz, Juanita L. Merchant

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Background & 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.

Original languageEnglish (US)
Pages (from-to)1025-1051
Number of pages27
JournalCMGH
Volume14
Issue number5
DOIs
StatePublished - Jan 2022

Keywords

  • Enteric Glia
  • Gastrinomas
  • Hedgehog Signaling
  • KIF3A
  • Primary Cilia
  • SOX10

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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