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FMRP Modulates Neural Differentiation through m6A-Dependent mRNA Nuclear Export

Brittany M Edens1, Caroline Vissers2, Jing Su1

  • 1Departments of Pediatrics, Neurology, and Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA.

Cell Reports
|July 25, 2019
PubMed

Insights

Fragile X mental retardation protein (FMRP) binds N-methyladenosine (m6A) modified mRNA, promoting its export from the nucleus during neural differentiation. This m6A-RNA export mechanism is crucial for normal neural development.

Area of Science:

  • Molecular Biology
  • Neuroscience
  • RNA Biology

Background:

  • N-methyladenosine (m6A) modification regulates RNA function.
  • Fragile X mental retardation protein (FMRP) is involved in neural development.

Purpose of the Study:

  • To investigate the role of FMRP in m6A-modified mRNA nuclear export during neural differentiation.
  • To elucidate the mechanism by which FMRP facilitates m6A-dependent RNA export.

Main Methods:

  • RNA sequencing (RNA-seq) and m6A sequencing (m6A-seq) were employed.
  • Fmr1 knockout (KO) and Mettl14 conditional KO (cKO) mouse models were utilized.
  • Functional assays assessed mRNA nuclear export and FMRP binding.

Main Results:

  • FMRP binds m6A-modified mRNAs and promotes their nuclear export via CRM1.
  • Fmr1 KO and Mettl14 cKO mice exhibit delayed neural progenitor cell cycle progression.
  • Both FMRP and m6A are essential for the nuclear export of specific target mRNAs involved in neural differentiation.

Conclusions:

  • FMRP plays a critical role in mediating m6A-dependent mRNA nuclear export.
  • This mechanism is vital for regulating neural differentiation and progenitor cell maintenance.
  • Defects in this pathway phenocopy aspects of Fragile X syndrome.
Keywords:
FMRPFmr1 knockoutMettl14RNA methylationfragile X syndromem(6)Aneural differentiationneural stem cellsnuclear exportnuclear-cytoplasmic transport

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