The cellular basis of FMRP function

脆性X染色体综合征是一种最常见的智力迟钝，可以遗传给孩子。的父母。它是由缺乏一种叫做脆性X智力迟钝蛋白或FMRP的蛋白质引起的。同样，产生FMRP的基因位于X染色体上。男性有一个X染色体副本，而女性有两个副本，每个副本都包含一个FMRP基因的副本。有趣的是，女性的两条x染色体表达的基因并不相同；在胎儿早期发育过程中，每个细胞似乎随机地决定使一条x染色体失活（这一过程被称为x染色体失活）。在患有FXS的女性中，如果一个细胞使含有正常基因的染色体失活，该细胞将不会产生FMRP。同样，如果细胞使含有突变FMR1基因的x染色体失活，细胞将产生正常水平的FMRP。由于x -失活是随机的，女性神经系统缺陷的严重程度取决于突变细胞和正常细胞的相对数量。在老鼠身上，我们可以利用雌性有正常和异常细胞的事实来了解FMRP是如何调节大脑发育的，以及这种疾病是否可以通过某些类型的药物治疗来治疗。例如，存在正常水平FMRP的细胞可能会分泌一些因子来拯救不表达FMRP的细胞。女性只有在正常细胞的比例过低而无法有效拯救突变细胞时才会出现症状。在这种情况下，确定救援发生的因素将为男性和女性FXS患者提供极好的前瞻性药物治疗。或者，正常细胞的存在可能无法拯救突变细胞，因为突变细胞没有能力对正常细胞产生的因子作出反应。在这种情况下，必须寻求替代形式的治疗，要么直接改变突变细胞的基因，要么可以绕过FMRP的正常作用。所有的实验都将集中在大脑皮层和海马体的神经元上，这是哺乳动物调节认知和记忆的大脑区域。因此，这些实验将指导未来对FXS治疗的研究。此外，他们将是第一个直接研究雌性FXS发育的实验。

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.