James W. Posakony
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The scientific interests of our lab
lie in the areas of pattern formation, cell fate specification, and
morphogenesis during development. The peripheral nervous system (PNS)
of the adult fruit fly (Drosophila melanogaster) has proven
to be a particularly accessible setting in which to investigate these
problems, and our research program is directed at understanding the
cellular and molecular mechanisms that control PNS development. We
employ a variety of experimental approaches, including classical and
molecular genetics, cell biology, and biochemistry, both to elucidate
the molecular mechanisms of action of various proteins and to assess
their in vivo developmental functions. At present our work
is focused on two broad questions: (1) How do cell-cell interactions
mediated by the Notch signaling pathway control alternative cell fate
decisions throughout sensory
organ development? (2) What are the specific molecular links between
the mechanisms that specify cell fate in the sensory organ lineage
and the execution of the cells' individual differentiative programs?
As alluded to above, the multiple binary cell fate decisions that characterize sensory organ development in the fly all involve cell-cell interactions mediated by the Notch signal transduction pathway. Activation of the Notch receptor protein by transmembrane ligands results in specific proteolytic release of the receptor's intracellular domain. In the nucleus, this domain interacts directly with the DNA-binding protein Suppressor of Hairless, forming a complex with transcriptional activation activity. Among the targets directly activated by Suppressor of Hairless are several genes of the Enhancer of split Complex.
A brief description of some of the current
major projects in the lab will convey a little of the flavor and excitement
of our work. (1) Recently, we have discovered a novel gene family
in Drosophila that appears to be important in the regulation
of Notch pathway activity. The five known members of the family all
encode small (78-158 aa) proteins that include domains predicted to
form highly basic amphipathic a-helices. Recently we have shown that
overexpression of any of these proteins interferes
specifically with Notch signaling-dependent cell fate decisions in
adult sensory organ development. (2) We have recently found that many
Drosophila genes involved in the regulation of neurogenesis
include an unexpectedly complex array of post-transcriptional regulatory
sequences in their 3' untranslated regions. Some of these appear to
be involved in the formation of RNA-RNA duplexes. We are currently
seeking to determine the detailed in vivo function of these elements
and to identify
the almost certainly novel protein factors that may interact with
them. (3) One of our long-term goals is to connect fundamental cell
fate specification pathways such as the Notch system with the genes
that function in the morphogenesis and terminal differentiation of
the individual cells of the sensory organ. We have begun pursuing
this problem in two ways: (a) working further downstream of the Notch
pathway by identifying new direct regulatory targets of Suppressor
of Hairless and of the
repressor proteins encoded by the Enhancer of split Complex, and (b)
identifying the transcriptional enhancer elements (and transcription
factors working through them) that direct cell type-specific gene
expression in the sensory organ lineage.
Barolo, S., Walker, R. G., Polyanovsky, A. D., Freschi, G., Keil, T., and Posakony, J. W. (2000). A Notch-independent activity of Suppressor of Hairless is required for normal mechanoreceptor physiology. Cell 103: 957-969.
Barolo, S., and Posakony, J. W. (2002). Three habits of highly effective signaling pathways: Principles of transcriptional control by developmental cell signaling. Genes & Dev. 16: 1167-1181. [Recommended by the Faculty of 1000]
Rebeiz, M., Reeves, N. L., and Posakony, J. W. (2002). SCORE: A computational approach to the identification of cis-regulatory modules and target genes in whole-genome sequence data. Proc. Natl. Acad. Sci. USA 99: 9888-9893.
Barolo, S., Stone, T., Bang, A. G., and Posakony, J. W. (2002). Default repression and Notch signaling: Hairless acts as an adaptor to recruit the corepressors Groucho and dCtBP to Suppressor of Hairless. Genes & Dev. 16: 1964-1976.
Reeves, N., and Posakony, J. W. (2005). Genetic programs activated by proneural proteins in the developing Drosophila PNS. Dev. Cell 8: 413-425.
Rebeiz, M., Stone, T., and Posakony, J. W. (2005). An ancient transcriptional regulatory linkage. Dev. Biol. 281: 299-308. [Recommended by the Faculty of 1000]
Castro, B., Barolo, S., Bailey, A. M., and Posakony, J. W. (2005). Lateral inhibition in proneural clusters: Cis-regulatory logic and default repression by Suppressor of Hairless. Development 132: 3333-3344. [Recommended by the Faculty of 1000]
Jim Posakony received his Ph.D. from the California Institute of Technology in 1982. Prior to coming to UCSD in 1985, hewas a postdoctoral fellow at Harvard University. In 1986 he was named a Pew Scholar, and currently serves on the editorialboards of Developmental Biology and Invertebrate Neuroscience.
