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Identification of FMRP target mRNAs in the developmental brain: FMRP might coordinate Ras/MAPK, Wnt/β-catenin, and

Cristine R Casingal1, Takako Kikkawa1, Hitoshi Inada1,2

  • 1Department of Developmental Neuroscience, United Center for Advanced Research and Translational Medicine (ART), Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.

Molecular Brain
|December 16, 2020
PubMed

Insights

Fragile X mental retardation protein (FMRP) regulates key genes in brain development. Its dysfunction impacts neurodevelopmental disorders like Fragile X syndrome (FXS), intellectual disability (ID), and autism spectrum disorder (ASD) by affecting signaling and epigenetic pathways.

Area of Science:

  • Neuroscience
  • Developmental Biology
  • Genetics

Background:

  • Corticogenesis is crucial for embryonic brain development and its disruption can lead to neurodevelopmental disorders.
  • Fragile X syndrome (FXS), characterized by intellectual disability (ID) and autism spectrum disorder (ASD), is linked to the Fragile X mental retardation protein (FMRP).
  • FMRP's precise role in brain development and its target molecules remain largely unelucidated.

Purpose of the Study:

  • To identify messenger RNA (mRNA) targets of FMRP in the developing mouse brain cortex.
  • To investigate the potential involvement of FMRP in epigenetic regulation during corticogenesis.
  • To explore the impact of FMRP dysfunction on key signaling pathways relevant to neurodevelopmental disorders.

Main Methods:

  • RNA immunoprecipitation sequencing (RIP-seq) was employed to identify FMRP-bound mRNAs in the embryonic mouse brain.
  • Bioinformatic analyses were performed to identify overlaps between FMRP targets and genes associated with ID and ASD.
  • Western blotting was used to assess mTOR signaling pathway activation in Fmr1 knockout mice.

Main Results:

  • 865 candidate FMRP target genes were identified, with significant overlap with known ID (126 genes) and ASD (118 genes) associated genes.
  • FMRP target genes were enriched in functions related to chromatin organization and histone modification, suggesting a role in epigenetic regulation.
  • A core set of 17 FMRP target genes involved in neurogenesis and associated disorders were identified, pointing to roles in Ras/MAPK, Wnt/β-catenin, and mTOR signaling pathways.
  • Overactivation of mTOR signaling was observed in the Fmr1 knockout mouse neocortex.

Conclusions:

  • FMRP plays a critical role in regulating mRNA targets during embryonic brain development.
  • Dysregulation of FMRP impacts epigenetic modifications and signaling pathways, contributing to neurodevelopmental disorders like FXS, ID, and ASD.
  • These findings provide novel insights into the molecular mechanisms underlying FMRP's function in the developing brain.
Keywords:
CorticogenesisFMRPFXSRNA binding proteinmRNA targets

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