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Michael J. Stern |
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| Associate Professor of Genetics; Director of Graduate Studies, Co-Director, MCGD Track (BBS) |
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* B.S. Yale College, 1981
* Ph.D. University of California, Berkeley, 1986
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| Research Interests: | |
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* Cell Migration Guidance
* FGF Signaling
* Muscle Development
* Computational Modeling of Biological Systems
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| The research in my laboratory is focused on three related topics: (1) describing the molecular
mechanisms that guide migrating cells; (2) elucidating fibroblast growth factor (FGF) receptor-mediated
signal transduction pathways; and (3) developing computer modeling methodologies for representing biological
systems. Using genetic screens, we have identified components involved in mediating FGF signaling as well as
genes involved in the mechanisms that guide the migrations of a pair of muscle precursor cells. By virtue of
their high level of structural and functional evolutionary conservation, our studies of these components help
elucidate their roles in higher multicellular animals. The FGF-regulated processes in C. elegans that we are
currently studying include the regulation of muscle differentiation, cell division, fluid homeostasis, and cell
migration guidance. Our studies on cell migration have elucidated the roles of guidance cues and their receptors
as well as molecules that alter the cytoskeletal architecture in response to outside guidance cues. In collaboration
with a group of computer scientists at the Weizmann Institute of Science in Israel, we have also begun to model the
development of the C. elegans egg-laying system to begin to integrate the tremendous amount of information about the
events underlying the development of this well-characterized system.
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| Current Research: | |
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Sex Myoblast Migration Guidance:
Cell migration is crucial for normal metazoan development. To gain a better understanding of some
of the mechanisms that guide migrating cells to their final destinations, we study the migrations of a pair
of cells known as sex myoblasts (SMs) in C. elegans hermaphrodites.
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| The SMs migrate anteriorly along the ventral body muscles to positions that flank the precise center of the developing gonad.
The SMs subsequently generate a set of vulval and uterine muscles that are required for egg laying. Each of two distinct mechanisms
propels the SMs anteriorly. A gonad-independent mechanism allows a coarse positioning of the SMs while a gonad-dependent signal
attracts the SMs to positions that flank the precise center of the gonad. Additional mechanisms function to restrict the migrations
of the SMs along the ventral muscle quadrants and keep the SMs from wandering dorsally (see Figure).
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| We have used a number of mutant screens to identify genes that are required for the normal migrations of the
SMs. Mutations in two genes, egl-17 and egl-15(EGg Laying defective), can cause dramatic SM migration defects even in
animals in which all the other mechanisms are cooperating to position the SMs properly. These genes encode a fibroblast
growth factor (FGF) and its tyrosine kinase receptor, respectively. Mutations in these genes abolish the gonad-dependent
attraction and reveal an underlying repulsion mechanism, thereby circumventing the normally cooperative gonad-dependent
and gonad-independent mechanisms. EGL-17/FGF appears to act as a chemoattractant that guides the SMs to their precise
final positions. Current efforts are aimed at understanding the events that occur downstream of EGL-15/FGFR to elicit
the proper movements of the SMs in response to EGL-17 and determining the nature of the repulsion mechanism.
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| Three genes (unc-53, unc-71, and unc-73) have been identified that are required for the gonad-independent
mechanism. The UNC-53 and UNC-73 proteins contain domains that suggest a role in modifying the cytoskeletal architecture
in response to outside guidance cues. The UNC-71 protein is a member of the ADAM metalloproteinase family, and appears
to act cell non-autonomously in the gonad-independent mechanism. We hope to understand how these genes function together
to mediate the gonad-independent mechanism and to identify the cues that direct this mechanism. Ultimately we would like
to understand how the SMs integrate the information that they receive from the various mechanisms to migrate accurately
and reproducibly.
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FGF Signal Transduction:
The EGL-15 FGF receptor tyrosine kinase is required for other processes in C. elegans besides
SM migration guidance. A second major function of EGL-15 is in the maintenance of internal fluid balance,
a function which is essential for viability.Using suppressor screens, we have identified components that
interact with EGL-15 to mediate this function. One of these, CLR-1 (CLeaR), functions to attenuate signaling
through the EGL-15 signaling pathway, and encodes a receptor tyrosine phosphatase. Since clr-1 mutants appear
to have excessive EGL-15 signaling, suppressors of the Clr phenotype of clr-1 mutants (or soc mutations) have
been used to identify components of the EGL-15 signal transduction pathway whose compromised function can
reduce signaling back to normal levels. The soc genes (see Figure) identify a set of proteins that transduce
the signaling event from the EGL-15 FGF receptor to the activation of a RAS/MAP kinase cascade. Current efforts
are aimed at understanding the molecular interactions among these components that allow strictly regulated
EGL-15 signaling. The high degree of similarity to human FGF receptor signaling pathways has allowed our
analysis of EGL-15 signaling to identify important novel components of receptor tyrosine kinase pathways
and to serve as an important basis for the understanding of FGF receptor signaling mechanisms in general.
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Muscle Development:
We have recently discovered additional roles for EGL-15 within the lineage that generates the egg-laying
muscles. These roles contribute to many fundamental biological processes which include cell division polarity and
the regulation of cell division. Hyperactivation of EGL-15 has revealed an additional ability of EGL-15 to inhibit
muscle differentiation. This last discovery has provided a model genetic system to analyze the inhibitory role of
FGFs in vertebrate myogenesis. A candidate gene approach has defined the role of a PI3Kinase signaling pathway
that promotes myogenesis in C. elegans, much as it does in vertebrate systems. Complementing this approach, a
genome-wide RNAi modifier screen is currently being conducted to identify novel factors involved in the myogenic
decision. We seek to understand how EGL-15 transitions between its various roles within this lineage and the
mechanisms that confer specificity to the outcome of FGF signaling in C. elegans.
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Modeling Development Using Tools Developed for the Analysis of Complex Reactive Systems:
Together with computer scientists at the Weizmann Institute of Science, we have been
developing computer modeling tools to simulate and analyze the behavior of developing organisms.
These tools allow modeling behaviors that we understand primarily using molecular/genetic data.
The object-oriented modeling tools we are using were originally designed to model the behavior of
complex reactive systems, and have been used in system design for the production of complex
man-made machines such as fighter planes and telecommunication systems. The many similarities
between our descriptions of developmental biology and the computer modeling descriptions of
behavior based on formal mathematical logic make this a reasonable approach for top-down modeling
of biological events.
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We have begun to model the development of the egg-laying system in C. elegans, incorporating
the complex sets of interactions that coordinate the development of this system. A graphical user interface
(GUI) has been designed that allows biologists to “play-in” biological scenarios of this system using
graphical representations that are in common use in biology. These scenarios, including both general
biological rules and the results of individual experiments, are translated into the high-level object-oriented
language of Live Sequence Charts, which are mathematically rigorous logic statements. Compelling IF-THEN
representations link these statements into an executable model, allowing simulation, querying possible
outcomes, and checking the logical consistency of the entire set of input data. The models are executable
even with only a small amount of input data. Efforts continue to input additional data, to create a more
sophisticated match between the biology and the model representation, and to develop new computer science
capabilities to expand the model. While many approaches to modeling biology exist, this one is unique in
that it allows the incorporation of existing and newly obtained genotype/phenotype or condition/result
types of data without necessitating an understanding of the underlying molecular mechanism. For additional
information, see the site: Formal Modeling, Simulation and
Analysis of C. elegans Developmnet
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| Model for Mechanisms Controlling SM Migration.
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| EGL-17/FGF serves as a chemoattractant emanating from multiple sources that reinforce the precise
positioning of the SMs. A gonad-dependent repulsion is revealed in the absence of EGL-17. A gonad-independent
mechanism also drives the SMs anteriorly, while another mechanism mediated by the SAX-3/Robo receptor aids in
keeping the SMs in the ventral muscle quadrants. Current investigations are aimed at understanding the molecular
basis of how these mechanisms are integrated.
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| Model for EGL-15/FGFR signal transduction.
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| Components implicated in EGL-15 signaling are diagrammed. The mechanisms utilized in transducing the
signal from EGL-15 to the activation of the RAS/MAPK cascade are the focus of current investigations.
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| Representative Publications: | | |
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Kokel, M., Borland, C.Z., DeLong, L., Horvitz, H.R, and Stern, M.J. clr-1
encodes a receptor tyrosine phosphatase that negatively regulates an FGF receptor signaling pathway in C. elegans. Genes
Dev. 12, 1425-1437, 1998.
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Mihaylova, V.T., Borland, C.Z., Manjarrez, L., Stern, M.J., and Sun, H. The
PTEN tumor suppressor homolog in C. elegans regulates longevity and dauer formation in an insulin-receptor like signaling pathway.
Proc. Natl. Acad. Sci. U.S.A. 96:7427-7432, 1999.
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| Borland, C.Z., Schutzman, J.L. and Stern, M.J. (2001). Fibroblast growth factor signaling in Caenorhabditis elegans. BioEssays 23, 1120-1130.
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Schutzman, J.L., Borland, C.Z., Newman, J.C., Robinson, M.K., Kokel, M. and Stern, M.J. (2001). The Caenorhabditis elegans EGL-15 signaling pathway implicates a DOS-like
multisubstrate adaptor protein in fibroblast growth factor signal transduction. Mol. Cell. Biol. 21, 8104-8116.
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Kam, N. Harel, D., Kugler, H., Marelly, R., Pnueli, A., Hubbard, E.J.A. and Stern, M.J. (2003) “Formal modeling of C. elegans development: a scenario-based approach.” In Proc. 1st Int. Workshop
on Computational Methods in Systems Biology (ICMSB 2003), C. Priami (ed.). Lecture Notes in Computer Science, Vol. 2602, Springer-Verlag, pp. 4-20.
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| Goodman, S.J., Branda, C.S., Robinson, M.K., Burdine, R.D. and Stern, M.J. (2003) “Alternative splicing affecting a novel domain in the C. elegans EGL-15
FGF receptor confers functional specificity.” Development 130:3757-3766.
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| Contact Information: | |
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Yale University School of Medicine
Department of Genetics
333 Cedar Street, I-354 SHM
P.O. Box 208005
New Haven, CT 06520-8005
U.S.A.
(203)737-2283 OfficePhone
(203)785-6333 FAX
(203)737-2279/2318 Laboratory
Michael.Stern@Yale.edu
Visit the Stern Lab
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