CGG repeats in the human FMR1 gene regulate mRNA localization and cellular stress in developing neurons

Cell Rep. 2024 Jun 25;43(6):114330. doi: 10.1016/j.celrep.2024.114330. Epub 2024 Jun 11.

Abstract

The human genome has many short tandem repeats, yet the normal functions of these repeats are unclear. The 5' untranslated region (UTR) of the fragile X messenger ribonucleoprotein 1 (FMR1) gene contains polymorphic CGG repeats, the length of which has differing effects on FMR1 expression and human health, including the neurodevelopmental disorder fragile X syndrome. We deleted the CGG repeats in the FMR1 gene (0CGG) in human stem cells and examined the effects on differentiated neurons. 0CGG neurons have altered subcellular localization of FMR1 mRNA and protein, and differential expression of cellular stress proteins compared with neurons with normal repeats (31CGG). In addition, 0CGG neurons have altered responses to glucocorticoid receptor (GR) activation, including FMR1 mRNA localization, GR chaperone HSP90α expression, GR localization, and cellular stress protein levels. Therefore, the CGG repeats in the FMR1 gene are important for the homeostatic responses of neurons to stress signals.

Keywords: 5′ UTR; CGG repeats; CP: Molecular biology; CP: Neuroscience; FMR1; FMRP; HSP90; RNA localization; dexamethasone; fragile X syndrome; glucocorticoid receptor; human-specific; neuron; pluripotent stem cells; single molecule FISH; stress; trinucleotide repeats.

MeSH terms

  • 5' Untranslated Regions / genetics
  • Fragile X Mental Retardation Protein* / genetics
  • Fragile X Mental Retardation Protein* / metabolism
  • HSP90 Heat-Shock Proteins / genetics
  • HSP90 Heat-Shock Proteins / metabolism
  • Humans
  • Neurons* / metabolism
  • RNA, Messenger* / genetics
  • RNA, Messenger* / metabolism
  • Receptors, Glucocorticoid / genetics
  • Receptors, Glucocorticoid / metabolism
  • Stress, Physiological / genetics
  • Trinucleotide Repeat Expansion / genetics
  • Trinucleotide Repeats / genetics

Substances

  • Fragile X Mental Retardation Protein
  • RNA, Messenger
  • FMR1 protein, human
  • Receptors, Glucocorticoid
  • 5' Untranslated Regions
  • HSP90 Heat-Shock Proteins