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

Author:

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

Abstract

ABSTRACTBACKGROUND & AIMSEfforts to characterize the signaling mechanisms that underlie gastroenteropancreatic neoplasms (GEP-NENs) are precluded by a lack of comprehensive model systems that recapitulate pathogenesis. Investigation into a potential cell-of-origin for gastrin-secreting NENs revealed a role for enteric glia in neuroendocrine cell specification. Here we investigated the hypothesis that loss of menin in glial cells stimulated neuroendocrine differentiation and tumorigenesis.METHODSUsing Cre-lox technology, we generated a conditional glial fibrillary acidic protein-directed Men1 knockout (GFAPΔMen1) mouse model. Cre specificity was confirmed using a tdTomato reporter. GFAPΔMen1 mice were evaluated for GEP-NEN development and neuroendocrine cell hyperplasia. siRNA-mediated Men1 silencing in a rat enteric glial cell line was performed in parallel.RESULTSGFAPΔMen1 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. Mechanistically, Men1 deletion induced reprogramming from a mature glial phenotype toward a neuroendocrine lineage. Furthermore, blockade of Hedgehog signaling in enteric glia attenuated neuroendocrine hyperplasia by restricting the neuroendocrine cell fate.CONCLUSIONSGFAP-directed Men1 inactivation exploits glial cell plasticity in favor of neuroendocrine differentiation.GRAPHICAL ABSTRACT

Publisher

Cold Spring Harbor Laboratory

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