The cellular basis of FMRP function

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Fragile X syndrome is the most common form of mental retardation that can be inherited from ones? parents. It is caused by the absence of a single protein called the fragile X mental retardation protein or FMRP. As the same implies, the gene that makes FMRP is located on the X chromosome. Men have one copy of the X chromosome whereas women have two copies, each containing a copy of the FMRP gene. Interestingly, the two X-chromosomes in females do not express their genes equally; during early foetal development each cell makes a decision to inactivate one X-chromosome (in a process known as X-inactivation) apparently at random. In the case of females with FXS, if a cell inactivates the chromosome containing the normal gene, the cell will not make FMRP. Similarly, if the cell inactivates the X-chromosome containing the mutant FMR1 gene, the cell will make normal levels of FMRP. Because X-inactivation is random, the severity of neurological defects in females varies depending on the relative number of mutant and normal cells. In mice, we can exploit the fact that females have normal and abnormal cells to learn about how FMRP regulates brain development and whether or not the disease is treatable to certain types of drug treatments. For example the presence of cells with normal levels of FMRP may secrete some factors that rescue the cells that do not express FMRP. Women would only show symptoms if the proportion of normal cells is too low to effectively rescue the mutant cells. In this case identification of the factors by which rescue occurs would provide excellent prospective drug therapies for male and female FXS sufferers. Alternatively, the presence of normal cells may not be able to rescue the mutant cells because the mutant cells do not have the ability to respond to factors made by the normal cells. In this case, alternative forms of treatments that either directly alter the genetics of the mutant cells or that can bypass the normal role of FMRP would have to be pursued. All of the experiments will focus on neurons of the cerebral cortex and hippocampus, brain regions that mediate cognition and memory in mammals. These experiments will therefore guide future research into treatments of FXS. Furthermore, they will be the first experiments to directly examine the development of FXS in females.