Xlinked Mental Retardation

Nonsyndromic MR in human patients is frequently associated with abnormal formation of dendritic spines. The characterization of inherited forms of MR, especially in patients suffering from X-chromosome linked MR, has supported the prominent role of rho family GTPases in establishing neuronal circuitry. Thus one putative GEF for rac and/or cdc42 (aPIX ), one GAP specific for rho (oligophrenin63), and one downstream target of cdc42 and rac (PAK364) have been shown to be mutated in affected patients. This led to the proposal that the dysregulation of small GTPase cycles, and therefore dysregulation of spine actin might be a common denominator in the pathogenesis of MR65. Indeed knockdown of oligophrenin or PAK3 expression in hippocampal neurons changes the structure of dendritic spines. Reduction of oligophrenin levels leads to a decrease in spine length, which can also be mimicked experimentally by constitutively active RhoA, suggesting that derepression of the rho/Rho kinase pathway may contribute to MR

in patients66. Suppression of PAK3 expression in neurons blocks spine maturation and leads to production of filopodial protrusions instead67. However, things may not be so straightforward, as the deletion of the PAK3 gene in mice does not lead to changes in the structure of the dendritic tree of hippocampal neurons, or changes in spine morphology68. PAK3 deficient mice do exhibit synaptic deficits, evident as a decrease in the late phase of LTP. However, these deficits are probably not due to a different regulation of the actin cytoskeleton, as the key step in this process, phosphorylation of cofilin, is not affected by loss of PAK3. Instead, the authors showed a decreased phosphorylation of the transcription factor CREB (cAMP responsive element-binding protein), which is known to contribute significantly to synaptic plasticity. The example of the PAK3 knockout mice demonstrates that there are probably many ways to generate deficits in synaptic plasticity and the cognitive abilities of mice or men, and interference with normal spine morphology may only be one of several aspects in the pathogenesis of MR.

Deficiencies in translational control at or near synapses have been implicated as a cause for the cognitive deficits associated with the fragile X mental retardation syndrome, which is the most frequent inherited form of MR. Patients exhibit loss of expression of FMRP due to a triplet repeat expansion in the promoter region of the gene. Consistent with studies on other molecules implicated in the pathogenesis of MR, the brains of mice lacking FMRP expression do exhibit irregular thin and elongated spines which are also the hallmark of MR patients69,70. FMRP is an RNA-binding protein which is implicated in translational repression of responsive mRNAs. One current view on FMRP is that its loss in MR patients or knockout mice leads to a translational derepression of certain target mRNAs. As the FMRP protein is present in dendrites, it is likely that especially local translational control in the dendrite is absent in patients. Recent work suggests that this might involve small nontranslated RNAs such as the BC1 (in rodents) or BC200 (in humans) as translational corepressors, both of which are also present in dendrites71. However, it has been a matter of debate which mRNAs are exactly controlled in their translational efficiency by the FMRP protein. A large group of mRNAs was found to be specifically associated with the FMRP protein in the brains of mice in vivo72. RNA binding by FMRP is favored by specific G-quartet sequence motifs within target mRNAs; association of these mRNAs with FMRP changed their translational status73. Other studies have provided additional lists of mRNAs which are associated with FMRP in neurons, with only limited overlap to the first study74. Studies on the related Drosophila protein (dFMR1) were helpful in this respect as it became clear that both the fly and the mammalian protein may associate with and regulate translation of the message coding for microtubule associated protein MAP1b (futsch in flies). MAPVo/futsch protein is required for development of neuronal morphology75. Nevertheless it remains unclear at present how the large number of mRNAs/proteins regulated by FMRP actually contributes to aberrant neuronal development or synapse formation.

An interesting link between the fragile X syndrome and those MR forms caused by mutations in rho GTPase regulators is constituted by the cytosolic FMRP interacting protein CYFIP1, also known as Sra-1 (specifically rac1 associated protein). As mentioned above, CYFIP1 is involved in a hetero-pentameric complex, including WAVE. Upon rac binding to CYFIP1, this complex dissociates, leading to activation of WAVE. Similarly, the interaction of

Drosophila CYFIP with dFMRP is disrupted by rac binding, potentially establishing control of the translational apparatus via a rac-CYFIP-FMRP pathway76. Thus, there may be a strong interdependence of MR gene products controlling the cytoskeleton, and FMRP having a translational control function. However, the role of CYFIP and its various associated proteins for the morphological and functional development of the mammalian nervous system has not been analyzed yet.

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