|Interaction between FMRP and PAK on synaptic morphology, function and animal behavior
by Mansuo Hayashi, 8/1/2005
Fragile X syndrome (FXS) results from the loss of expression of the FMR1 gene. Studies in FMR1 knockout mice and FXS patients demonstrated critical roles for FMR1 in regulating synaptic morphology and function. Though little is known about how FMRP exerts these effects, FMRP binds certain RNAs and can block the synthesis (translation) of their encoded proteins, some of which are critical for the formation and maintenance of synaptic structure.
To gain further insights into FMRP's functional mechanism, the goal of this research is to identify new signaling pathways that regulate or interact with FMRP. Our hypothesis is that p21-activated kinase (PAK), a well-known regulator of cytoskeleton and synaptic structure, may antagonize FMRP (e.g. by relieving FMRP-mediated translational repression) to regulate synaptic morphology and function. As we previously found in transgenic mice with reduced PAK activity, neurons show fewer dendritic spines and a lower proportion of the longer and thinner spines compared to normal mice. In contrast, neurons in FMR1 knockout mice and FXS patients show more spines and a higher proportion of the longer and thinner spines.
Our preliminary data have indicated genetic and physical interactions between FMRP and PAK. We are investigating how FMRP and PAK affect each other's subcellular localization and activity. Since FMRP and PAK were known to regulate protein synthesis and cytoskeleton, respectively, this research may provide new insights into how FMRP and PAK coordinate these two cellular events in order to modulate synaptic morphology and function. This will advance our understanding on the molecular mechanisms underlying FXS and may lead to identification of new drug targets and genetic treatments for FXS