NMD abnormalities during brain development in the Fmr1-knockout mouse model of fragile X syndrome

Genome Biol. 2021 Nov 16;22(1):317. doi: 10.1186/s13059-021-02530-9.


Background: Fragile X syndrome (FXS) is an intellectual disability attributable to loss of fragile X protein (FMRP). We previously demonstrated that FMRP binds mRNAs targeted for nonsense-mediated mRNA decay (NMD) and that FMRP loss results in hyperactivated NMD and inhibition of neuronal differentiation in human stem cells.

Results: We show here that NMD is hyperactivated during the development of the cerebral cortex, hippocampus, and cerebellum in the Fmr1-knockout (KO) mouse during embryonic and early postnatal periods. Our findings demonstrate that NMD regulates many neuronal mRNAs that are important for mouse brain development.

Conclusions: We reveal the abnormal regulation of these mRNAs in the Fmr1-KO mouse, a model of FXS, and highlight the importance of early intervention.

Keywords: Cerebellum; Cortex; Fmr1-KO mouse; Fragile X protein (FMRP), Upframeshift protein 1 (UPF1); Fragile X syndrome; Hippocampus; Mouse brain development; Nonsense-mediated mRNA decay (NMD).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / growth & development*
  • Brain Diseases / genetics*
  • Cerebral Cortex / metabolism
  • Disease Models, Animal
  • Fragile X Mental Retardation Protein / genetics*
  • Fragile X Syndrome / genetics*
  • Hippocampus / metabolism
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurons / metabolism
  • Nonsense Mediated mRNA Decay / genetics*


  • FMR1 protein, human
  • Fmr1 protein, mouse
  • Fragile X Mental Retardation Protein