Emma Raff Jakoi
Instructor, Medical Center in the Department of Cell Biology
Activated synapses direct cellular differentiation of CNS neurons. This process requires the spatial distribution of specific proteins to establish cellular polarity (axon Vs dendrite) and to restructure functional micro-domains such as synapses. While the details of intracellular events connecting synaptic activation and the cellular response are largely unknown, localization of mRNA within dendrites has emerged as one means by which protein expression can be regulated locally. This process involves the formation of mRNA-ribonucleoprotein particles (RNP) that can associate with the cytoskeleton for movement. Our recent searches for common mediators and cis-acting signals encoded by these localized mRNAs have revealed a common motif, the Y element, which is bound by translin (testis-brain RNA binding protein). In functional assays, antisense oligonucelotides (anti-ODN) to this Y element disrupted translin-RNP formation in vitro and dendritic targeting of two localized mRNAs, ligatin and Ca++-calmodulin dependent kinase II (CAMKII), as well as expression of their cognate proteins within dendrites of cultured hippocampal neurons. Disruption of CAMKII mRNA localization but not of ligatin mRNA also occurred in hippocampal neurons in which kinesin I motor protein was suppressed, implicating kinesin I and at least one other motor protein in this process. Because these two mRNAs seemed to be delivered to individual synapses independently, we sought the identities of the motor proteins associated with translin –RNP complexes from rat hippocampus. Using sedimentation analyses, anti-ODN pull downs, and Western blotting, we found that whereas recombinant translin migrates as a 6S species, translin-RNP complexes are heterogeneous in size (12S and > 23S) and mRNA composition, and that from specific subclasses, translin co-precipitated with either kinesin I or kinesin II (KIF3) motor proteins. Our findings suggest that recruitment of motor proteins provides a mechanistic link by which heterogeneous RNP complexes may be sorted for independent delivery to activated synapses allowing for synaptic restructuring independent of nuclear control. These studies and those of others provide insight into the early structural and functional changes that underlie short-term memory and differentiation of individual synaptic contacts critical for the social interactions of neurons.
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