Astroglial FMRP deficiency cell-autonomously up-regulates miR-128 and disrupts developmental astroglial mGluR5 signaling

Yuqin Men, Liang Ye, Ryan D. Risgaard, Vanessa Promes, Xinyu Zhao, Martin Paukert, Yongjie Yang

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

The loss of fragile X mental retardation protein (FMRP) causes fragile X syndrome (FXS), the most common inherited intellectual disability. How the loss of FMRP alters protein expression and astroglial functions remains essentially unknown. Herewe showed that selective loss of astroglial FMRP in vivo up-regulates a brain-enriched miRNA, miR-128-3p, in mouse and human FMRP-deficient astroglia, which suppresses developmental expression of astroglial metabotropic glutamate receptor 5 (mGluR5), a major receptor in mediating developmental astroglia to neuron communication. Selective in vivo inhibition of miR-128-3p in FMRP-deficient astroglia sufficiently rescues decreased mGluR5 function, while astroglial overexpression of miR-128-3p strongly and selectively diminishes developmental astroglial mGluR5 signaling. Subsequent transcriptome and proteome profiling further suggests that FMRP commonly and preferentially regulates protein expression through posttranscriptional, but not transcriptional, mechanisms in astroglia. Overall, our study defines an FMRP-dependent cellautonomous miR pathway that selectively alters developmental astroglial mGluR5 signaling, unveiling astroglial molecular mechanisms involved in FXS pathogenesis.

Original languageEnglish (US)
Pages (from-to)25092-25103
Number of pages12
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number40
DOIs
StatePublished - Oct 6 2020

Keywords

  • Astroglia
  • FMRP
  • Fragile X syndrome
  • MGluR5
  • MiR-128

ASJC Scopus subject areas

  • General

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