Study Underscores Critical Role of FMRP in Brain Development

A study in mice has identified 865 gene targets of the fragile X mental retardation protein (FMRP) — which is missing in people with fragile X syndrome — including more than 100 linked to autism and intellectual disability (ID). 

Several FMRP targets associated with both autism and ID were also involved in nerve cell production (neurogenesis) during brain development. One such target, Mtor, showed increased activity in FMRP-deficient mice, indicating a potential role in the abnormal brain development seen in fragile X.

“Our study illustrated the possible molecular mechanism that causes [fragile X] in the fetal brain and furthers our understanding of hereditary developmental disorders in the brain’s developmental stage,” Noriko Osumi, PhD, professor of Tohoku University and lead investigator, said in a university press release.

The study, “Identification of FMRP target mRNAs in the developmental brain: FMRP might coordinate Ras/MAPK, Wnt/β-catenin, and mTOR signaling during corticogenesis,” was published in the journal Molecular Brain.

Brain development is a highly organized and complex process, in which even a minor disruption may have significant effects and result in neurodevelopmental disorders such as fragile X, a main genetic cause of autism spectrum disorder (ASD) and ID. 

Specifically, fragile X is caused by defects in the FMR1 gene that result in abnormal brain development. FMRP, the protein produced from FMR1, is involved in the maturation of so-called radial glial cells (RGCs) that produce many of the neurons populating the neocortex, a brain region that controls cognitive functions like perception and decision-making. Prior research suggested that lacking this protein affects the migration of neurons to form brain circuits.

Understanding the precise function of FMRP and the genes it regulates may provide insight into the underlying cause of multiple neurodevelopmental disorders. The research team sought to identify genes targeted by FMRP that are also associated with ASD and ID. In embryonic mice, they found that FMRP was highly expressed in the brain and specifically in RGCs, consistent with previous studies.

Using next-generation sequencing, a technique that enables rapid analysis of the genetic code, the researchers identified 865 potential FMRP target genes, many with functions related to brain development and, specifically, neurogenesis. A total of 126 of the identified FMRP targets were related to ID and 118 to ASD. Interestingly, the targets overlapped with genes involved in epigenetic regulation, a means of controlling gene activity without altering the DNA sequence.

These results indicate that FMRP may regulate genetic targets related to ID and ASD through epigenetic modifications.

A group of 17 FMRP “core” target genes was associated with neurogenesis, ID, and ASD. Among the core targets were genes involved in signaling pathways critical during brain development. One target in particular, Mtor (MTOR in humans), has previously been linked to both fragile X and ASD. In embryonic mice lacking FMR1 activity, signaling from the resulting mTOR protein was elevated in the neocortex, suggesting that it may contribute to the abnormal brain development seen in fragile X.

“Our results provide further insight into the critical roles of FMRP in the developing brain, where dysfunction of FMRP may influence the regulation of its … targets affecting signaling pathways and epigenetic modifications,” the investigators wrote.