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Faculty
Elisa Barbarese
Professor of Neuroscience
Barbarese@nso2.uchc.edu
Areas of interest:
Neural cell biology, myelin biogenesis, RNA
trafficking.
Our laboratory studies the mechanism and regulation of mRNA
transport, localization, and translation in oligodendrocytes and
neurons. RNA trafficking is essential to the formation of myelin. One of
the main transported mRNAs is that for myelin basic protein. Myelin
basic protein is a structural component of myelin endowed with membrane
adhesive properties. It is postulated that its synthesis takes place in
the myelin compartment in order to avoid deleterious consequences of
random membrane-membrane juxtaposition in the cell body. The transport
signal present in myelin basic protein mRNA is an 11 nucleotides
sequence that is recognized by heterogeneous nuclear ribonucleoprotein
A2. Similar transport signal sequences are present in other mRNAs, most
notably some shown to be localized in the dendrites of neurons. The
proteins encoded by these transported mRNAs have been implicated in
synaptic plasticity which underlies long-term potentiation and memory.
We have shown that the RNA trafficking pathway that we have uncovered in
oligodendrocytes, the A2RE/hnRNP A2 pathway, is functional in neurons.
We are currently analyzing the function of proteins identified in a
yeast two-hybrid screen that are associated with the RNA transport
complexes. These studies are done in primary neural cell cultures using
a battery of molecular, cellular, and microscopic approaches.
Lab Rotation Projects:
Regulation of translation of messages that are translated at sites
distant from the cell body.
Messenger RNAs that are synthesized in the myelin compartment of
oligodendrocytes or in dendrites of neurons are kept silent until they
reach their final destination. We have identified some of the components
involved in silencing mRNAs during their transport. The project will
involve analyzing how these components of the transport machinery and
those of the translation machinery interact with each other in a
coordinated manner. Protein-protein interactions are studied in vitro,
in cell extracts, and in live cells using fluorescently tagged
molecules. Transport and translation assays are done in cultured
oligodendrocytes and/or neurons before and after treatments with drugs,
antibodies, or RNAi that target specific components of the transport or
translation systems, and are monitored by fluorescence confocal
microscopy.
Characterization of the nervous system of a conditional TOG
knockout mouse.
TOG (tumor overexpressed gene) is a microtubule-associated protein. It
is found in granules that transport various mRNAs to specialized
compartments for translation. A major component of central nervous
system myelin is myelin basic protein (MBP) whose mRNA is transported
down oligodendrocyte processes to its final myelin destination.
Knockdown experiments done in cultured oligodendrocytes have indicated
that TOG is necessary for the translation of MBP mRNA. The mechanism by
which TOG affects translation is unknown. Previous studies have shown
that deletion of the MBP gene prevents myelin formation and results in a
neurological phenotype in mice homozygous for the shiverer mutation. The
absence of TOG and subsequently the absence of MBP should result in a
similar phenotype. We have generated conditional TOG knockout mice using
the cre-lox system in order to obtain mice in which TOG expression can
be abolished specifically in oligodendrocytes. Characterization of these
mice will be carried out at the behavioral, cellular and molecular
levels in order to identify the role and mode of action of TOG.
Laboratory Page
Publications
Selected Publications:
Kosturko LD, Maggipinto MJ, Korza G, Lee JW, Carson JH, Barbarese E.
Heterogeneous nuclear ribonucleoprotein (hnRNP) E1 binds to hnRNP A2 and
inhibits translation of A2 response element mRNAs. Mol Biol Cell. 2006
Aug;17(8):3521-33.
Kosturko LD, Maggipinto MJ, D'Sa C, Carson JH, Barbarese E.
The microtubule-associated protein tumor overexpressed gene binds to the
RNA trafficking protein heterogeneous nuclear ribonucleoprotein A2. Mol
Biol Cell. 2005 Apr;16(4):1938-47.
Maggipinto, A., Rabiner, C., Kidd, G.J., Hawkins, A.J., Smith, R.,
and Barbarese, E. Increased expression of the MBP mRNA binding protein
hnRNP A2 during oligodendrocyte differentiation. J. Neurosci. Res.
75:614-623 (2004).
Shan, J, Munro T.P., Barbarese, E., Carson, J.H., and Smith, R. A
molecular mechanism for mRNA transport in neuronal dendrites. J.
Neurosci.23:8859-8866 (2003).
Song, J., Carson, J.H., Barbarese, E., Li, F.Y., and Duncan, I.D.
Anterograde RNA transport is inhibited in microtubule defective
oligodendrocytes. Mol. Cell Neurosci. 24:926-938 (2003).
Huang, Y.S., Carson, J.H., Cao, Q., Barbarese, E., and Richter, J.D.
Facilitation of dendritic mRNA transport by CPEB. Genes & Development
17:638-653 (2003).
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