Our research interest is to understand relation between developmental disorder and local translation in neurons.  Neurons have very long neuronal processes.  At apical portions of the processes, the system regulating local translation exists semi-independent from cell bodies containing nuclei.  Namely, the peripheral processes including growth cones and synapses determine timing of local translation by themselves, independent from cell bodies, like decentralization from central government. RNA binding proteins and microRNAs play important roles in this system regulating local translation.  Aberrant regulation of local translation at peripheral processes of neurons is considered to affect morphology and function of synapses, and may lead to developmental disorders including mental retardation and autism.  We will elucidate the relationship between the translational regulatory mechanism at the peripheral processes and the morphology and function of neurons in fragile X syndrome, an inherited developmental disorder. 

1. Local translation & presynaptic functions in neurons of fragile X syndrome

FMRP, which is a causative gene product of fragile X syndrome, is an RNA-binding protein that regulates translation. We found that in a disease model mouse (Fmr1-KO) lacking the causative gene, local translation of specific proteins (including Munc18-1) in the presynapses is increased, and presynaptic function is enhanced (above Figure, left).  We would like to clarify the pathophysiology of fragile X syndrome by studying the FMRP-mediated regulatory mechanism in presynapses.

2. Stress responses in neurons of fragile X syndrome

Because oxidative stress is increased in the fragile X syndrome model (Fmr1-KO) mice, it is considered that neurons are more stressed than wild type.  It is known that in response to stress, stress granules composed of mRNAs and RNA-binding proteins are formed in the cells to stop unnecessary translation and exert stress tolerance.  Since Fmr1-KO mice do not express FMRP that is one of the constituent factors of stress granules, we consider that formation of stress granules reduces and that stress tolerance decreases.

3. Axonal microRNAs and translational regulation

MicroRNAs, which are small non-coding RNAs (around 20-25 bases), are known to bind to mRNAs to control translation.  We found that specific microRNAs localize to the peripheral axons of neurons.  We are now trying to elucidate whether these microRNAs regulate local translation in axons, as well as translation in neighboring cells, to regulate their functions.