|Rac-dependent regulation of neuronal morphology in Fragile X
by MariVi Tejada-Simon, 8/1/2008
It is well known that Rac, a member of the Rho family of small GTPases, plays a key role in the formation, maturation and maintenance of dendritic spines in neurons. Neuronal plasticity requires actin cytoskeleton remodeling and local protein translation in response to synaptic activity. The shape and density of actin-rich dendritic spines is altered in patients with Fragile X syndrome (FXS) as well as in Fmr1 knockout mice.
Recently it has been reported that FMRP (protein missing in Fragile X) has a connection to Rac at least in fibroblasts. In these cells, absence of FMRP induces an atypical development of actin remodeling by bringing up levels of proteins such as Rac, as well as Rac downstream effectors PAK, CYFIP1 and also PP2A. Consistent with these observations, specific neurons of transgenic mice that overexpress Rac showed an abnormal structure of their dendritic spines.
We believe that under normal conditions, FMRP may act as a negative regulator on the synthesis and/or transport of proteins involved in the actin cytoskeleton such as Rac. This function likely maintains an optimal level of the protein and facilitates the reorganization of the cytoskeleton leading to normal changes in neuronal morphology during activity-dependent plasticity. In contrast, in Fmr1 knockout mice (animal model of FXS), lack of FMRP may induce an excessive synthesis of Rac, leading to abnormal Rac-induced actin remodeling, which in turn may generate the anomalies reported in the structure and possibly in function of dendritic spines, resulting in cognitive deficiencies.
Our laboratory is testing this hypothesis using Fmr1 knockout mice model. If this alteration in Rac exists, we will determine whether pharmacological or genetic manipulation of Rac in these animals can rescue the cellular and behavioral abnormalities observed.