The main research interest of our laboratory is to understand the mechanism
and function of mRNA transport and local protein synthesis in neurons of the
central and peripheral nervous system. We are using in vitro and in vivo models
of synaptic activity and nerve injury, as well as mouse models of neurological
diseases, to assess the function of mRNA regulation in axon guidance, nerve
regeneration and synaptic plasticity. We have a long-standing interest in the
mechanism, regulation and function of beta-actin mRNA localization to growth cones
of developing axons. More recently, we have been interested how impairments in
mRNA regulation may underlie spinal muscular atrophy (SMA) and fragile x syndrome
(FXS), two inherited neurological diseases affecting children. Efforts are also
underway to evaluate different therapeutic modalities in these mouse models.
Our research utilizes a multi-disciplinary approach that involves primary
neuronal culture, brain/nerve micro-dissection, viral vectors, fluorescently
tagged mRNA and proteins, fluorescence live-cell imaging, and molecular and
biochemical methods to isolate and characterize RNA-protein interactions. These
studies will provide new insight into molecular and cellular mechanisms important
for neuronal development and plasticity, as well as into defects in these pathways
that underlie neurological diseases.
Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function
Bassell and Warren, Neuron 2008, 60(2):201-14
The stimulated travels and function of FMRP throughout the neuron
FMRP is in a complex with several translationally arrested mRNAs at the synapse.
Following mGluR stimulation, FMRP-target mRNAs are rapidly derepressed, allowing
for local translation. A second phase of FMRP-dependent plasticity is shown that
involves the subsequent transport of new mRNAs from the cell body into dendrites.
(1) Upon mGluR1/5 activation, PP2A is rapidly activated and dephosphorylates FMRP,
thereby allowing for (2) local translation of proteins that affect synaptic function.
Following mGluR activation, FMRP is rephosphorylated by S6K1 with slower kinetics,
leading to translational repression. (3) The local degradation of FMRP by
ubiquitination may be involved in translational regulation at the synapse.
(4) There may be a retrograde signal (5) possibly involving FMRP shuttling into
the nucleus. (6) FMRP acts as a kinesin adapter to facilitate mRNA transport.
(schematic by Sharon Swanger)