Molecular mechanisms: FMRP target linked to cognitive skills
The protein missing in people with fragile X syndrome may activate the expression of a signaling protein dubbed NOS1 during prenatal development of brain regions involved in language and social skills, according to a study published 11 May in Cell1.
This regulation is evolutionarily conserved among great apes and humans, but is absent in mice, suggesting that defects in NOS1 could be linked to the higher-level cognitive deficits seen in fragile X syndrome.
Fragile X syndrome is characterized by intellectual disability, language delay and, often, autism. It is caused by the loss of the FMRP protein, which typically stalls the machinery that translates genetic messages, or mRNAs, into proteins. Many of FMRP’s targets are also autism candidates, providing a link between the two disorders.
In the new study, researchers show that FMRP induces NOS1 expression by binding directly to a repeating series of base pairs in the NOS1 mRNA. Postmortem brains from individuals with fragile X syndrome have significantly lower levels of NOS1 protein than do those from controls.
This interaction between FMRP and NOS1 may be important during key stages of fetal development when synapses, the junctions between neurons, are forming in the brain, according to the study.
The researchers found that the mRNA for NOS1 is present throughout postmortem brains from all ages, ranging from embryos just post-conception through adulthood. The mRNA is expressed in particular in pyramidal neurons, which activate signals in the cortex, a brain region involved in higher-order cognitive function. However, the finished protein is present only in certain regions of the cortex and at certain times, overlapping with FMRP expression.
For example, NOS1 and FMRP are both expressed 15 to 20 weeks after conception, and then decrease by week 23, in the frontoparietal operculum. This region later becomes Broca's area and the orofacial motor cortex, which are involved, respectively, in language comprehension and the recognition of movement, both of which are impaired in people with fragile X syndrome.
NOS1 and FMRP expression also spike at late stages of fetal development in the anterior cingulate cortex. This region is involved in decision-making, attention and emotion processing, all of which go awry in fragile X syndrome.
Interestingly, NOS1 expression is not restricted in the developing mouse brain, the study found. And the mouse version of the gene does not contain sequences that bind FMRP. These sequences are present in rhesus macaques and chimpanzees, however, suggesting that they are an evolutionary adaptation, and that the gene is involved in higher-order cognitive function.
1: Kwan K.Y. et al. Cell 149, 899-911 (2012) PubMed