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bioRxiv · 10.1101/2022.02.10.479845

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

Duan, S.·Sawyer, T. W.·Sontz, R. A.·Wieland, B. A.·Diaz, A. F.·Merchant, J. L.
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Abstract

BACKGROUND & 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 (GFAP{Delta}Men1) mouse model. Cre specificity was confirmed using a tdTomato reporter. GFAP{Delta}Men1 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. RESULTSGFAP{Delta}Men1 mice developed pancreatic NENs, in addition to pituitary prolactinomas that phenocopied the human MEN1 syndrome. GFAP{Delta}Men1 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 O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=65 SRC="FIGDIR/small/479845v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@1118702org.highwire.dtl.DTLVardef@1b6cc3forg.highwire.dtl.DTLVardef@1b4949org.highwire.dtl.DTLVardef@168704b_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Duan, S., Sawyer, T. W., Sontz, R. A., Wieland, B. A., Diaz, A. F., Merchant, J. L.. 2022-02-10. GFAP-directed Inactivation of Men1 Exploits Glial Cell Plasticity in Favor of Neuroendocrine Reprogramming. https://doi.org/10.1101/2022.02.10.479845

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