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C. Smibert
Associate Professor
B.Sc., (Biology), McMaster University,
1986
Ph.D., (Biology), McMaster University,
1994
Stanford University, Stanford, CA, 1995-99
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Medical Sciences
Building, Room 5344
416-946-5538
c.smibert@utoronto.ca |
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Translational Regulation
During Development
Research Synopsis
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Specification of various cell and tissue types relies
on differential patterns of gene expression which
are often controlled at the level of transcription.
Regulation, however, does not cease once transcripts
are made. Instead, a variety of post-transcriptional
control events, including translational controls,
may also contribute to proper expression patterns.
For example, recent studies have shown that selective
translational controls operate in such diverse processes
as red blood cell development and spermatogenesis
in mammals, sex determination in C. elegans, and dosage
compensation in Drosophila. Although these results
highlight the fact that translational controls are
likely to function in a wide range of developmental
processes, little is known about the molecular mechanisms
that underlie selective translational regulation.
Several of the most prominent examples of translational
controls have been revealed by studying the expression
of mRNAs that direct early Drosophila development.
For example, nanos (nos) protein, which directs posterior
body patterning in Drosophila, is localized to the
posterior of the embryo through the coordinate action
of systems that regulate the translation, localization,
and stability of nos mRNA.
Our long-term goals are to identify factors that regulate
and coordinate post-transcriptional control of nos
expression. We employ a combination of genetic and
biochemical approaches to pursue these investigations.
The ability to apply both genetics and biochemistry
to a problem is one of the advantages of the Drosophila
system. In addition, the use of Drosophila allows
one to readily explore the biological significance
of processes in a complex multicellular organism.
To date we have identified cis-acting sequences in
the 3' untranslated region (UTR) of the nos mRNA that
are required to repress nos translation. We have also
cloned a sequence specific RNA-binding protein, which
we call Smaug (Smg), that interacts with these sequences
to repress nos translation and subsequently degrade
nos mRNA. In addition, activation of nos translation
at the posterior appears to involve blocking Smg function.
The identification of Smg will allow us to begin to
answer basic questions about how translation is regulated,
and the fact the we have also identified potential
mouse and human Smg homologues suggests that our work
may be directly relevant to mammalian development.
Future work will focus on understanding
1) how Smg protein bound to the 3' UTR of an mRNA
is able to repress translation,
2) how Smg triggers specific decay of target mRNAs,
3) how Smg function is blocked at the posterior and
4) the role that Smg plays in Drosophila development.
This last question is especially intriguing since
our work suggests that Smg is expressed in the fly's
central nervous system raising the possibility that
Smg plays a role in nervous system function.
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Selected Publications
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Drosophila maternal Hsp83 mRNA destabilization is directed by multiple cis-elements
including a major, SMAUG-dependent, open-reading-frame element that functions independent
of translation. Semotok, J.L., Coopperstock, R.L. Luo, H. Karaiskakis, A. Vari, H.K.,
Smibert, C.A. and H.D. Lipshitz, (2008). Mol Cell Biol. 28:6757-72.
S. cerevisiae Vts1p induces deadenylation-dependent transcript degradation and interacts
with the Ccr4p-Pop2p-Not deadenylase complex. Rendl L.M., Bieman M.A. and C.A. Smibert.
(2008). RNA 14:1328-36.
A multiprotein complex that mediates translational enhancement in Drosophila. Nelson
M.R., Luo H., Vari H.K., Cox B.J., Simmonds A.J., Krause H.M., Lipshitz H.D., and C.A.
Smibert. (2007). J Biol Chem. 282:34031-8.
SMAUG is the major regulator of maternal mRNA destabilization in Drosophila and is
translationally activated by the PAN GU kinase. Tadros W., Goldman A.L., Babak T.,
Menzies F., Vardy, L., Orr-Weaver T., Hughes T.R., Westwood J.T., Smibert C.A. and H.D.
Lipshitz. (2007) Developmental Cell 12:143-155.
Sequence-specific recognition of RNA hairpins by the SAM domain of Vts1p. Aviv T., Lin
Z., Ben-Ari G., Smibert C.A. and F. Sicheri. 2006. Nat. Struct. Mol. Biol 13:168-76.
Mechanisms of Translational Regulation in Drosophila. Wilhelm, J.E. and C.A. Smibert.
(2005). Biology of the Cell 97: 235-252.
Smaug Recruits the CCR4/POP2/NOT Deadenylase Complex to Trigger Maternal Transcript Localization in the Early Drosophila Embryo. Semotok, J. L., Cooperstock, R. L., Pinder, B. D., Vari, H. K., Lipshitz, H. D., and
Smibert, C. A. (2005). Curr Biol 15, 284-294.
Drosophila Cup is an eIF4E binding protein that functions in Smaug-mediated translational repression. Nelson, M.R., Leidal, A.M., and Smibert, C.A.
(2004). EMBO J. 23: 150-159.
The RNA-binding SAM domain of Smaug defines a new family of
post-transcriptional regulators. Aviv, T., Lin, Z., Lau, S., Rendl, L.M.,
Sicheri, F., and Smibert, C.A. (2003). Nat. Struct. Biol. 10: 614-621.
Mechanisms of RNA localization and translational regulation.
Lipshitz, H.D. and Smibert, C.A. (2000). Curr. Opin.
Genet. Dev. 10, 476-488.
Smaug, a novel and conserved protein, contributes to
repression of nanos mRNA translation in vitro. Smibert,
C.A., Lie, Y.S., Shillinglaw W., Henzel W.J., and
Macdonald, P.M. (1999). RNA 5: 1535-1547.
Smaug protein represses translation of unlocalized
nanos mRNA in the Drosophila embryo. Smibert, C.A.,
Wilson, J.E., Kerr, K., and Macdonald, P.M. (1996).
Genes & Dev. 10, 2600-2609.
Translational regulation of maternal mRNAs. Macdonald,
P.M., and Smibert, C.A. (1996). Curr. Opin. Genet.
Dev. 6, 403-407.
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