|Transport, anchoring and translation of FMRP-associated mRNAs
by Vladimir Gelfand and Shuo-Chien Ling, 1/1/2006
Localized protein synthesis in dendritic compartments of a neuron is one of the mechanisms contributing
to learning and memory. For localized translation to occur, mRNA has to be delivered to and anchored at
the proper location. FMRP is a RNA-binding protein that binds to a specific subset of mRNAs and regulates
the expression of its target mRNAs. However, how FMRP regulates the processes among mRNA transport, anchoring,
and translation are not known.
We study the transport mechanisms for FMRP and its associated mRNAs. FMRP and mRNAs form granule-like structures
that are transported into dendrites. It has been shown that the transport of FMRP-RNP granules is dependent
on microtubules. Analyzing transport, we discovered that the bi-directional movement of FMRP granules are powered
by two microtubule motors: kinesin-1 and cytoplasmic dynein (Proc Natl Acad Sci U S A. 2004(101):17428-33).
In addition, the bi-directional transport of FMRP granules provides a mechanistic advantage to deliver mRNAs.
We are now investigating how this movement is regulated.
Furthermore, it is generally believed that the translation of mRNA in granules is repressed during transport.
When mRNA is delivered into spines, transport stops and translation is activated. Little is known of how this
transition occurs. We are also investigating what components are important for the anchoring process and how
transport and anchoring are related to translation. Finally, it is essential to understand how neuronal activities
(specifically, metabotropic glutamate receptor signaling cascades) influences and regulates this process.
The main goal of this research is to understand the mechanisms of localization-translation coupling of dFMRP-RNP
and how mGluR regulates this process. We believe that it will help to identify therapeutically useful targets.