Research Themes within the DBRI:

While there are numerous collaborations and no formal subdivisions within the DBRI, its research can be usefully described in terms of the five model organisms presently being studied:

Cell and molecular biology of yeast:
turning the power of genomics toward understanding the biology of the eukaryotic cell.

Jackie Vogel’s group exploits another major advantage of the yeast system, Saccharomyces cerevisiae, its particular utility as a unicellular eukaryote for the study of the basic mechanisms of cell biology. The Vogel group investigates the regulation of microtubule organization and function. Spindle and aster structures, essential to organizing chromosomes at mitosis, are composed of microtubules. Microtubules are polarized structures with plus and minus ends that are involved in both establishing spatial asymmetries and in transporting molecular complexes within cells. The Vogel group has made groundbreaking discoveries into how plus end proteins are regulated and localized.

Drosophila melanogaster: a system for understanding control of cell growth and proliferation, intercellular signaling, cell adhesion and the regulation of protein deployment in an asymmetric cell.

The fly ovary is a superb system for studying intercellular signaling and cell asymmetry. In response to various signals from the underlying germline, the follicular epithelium undergoes a highly stereotyped pattern of differentiation, cell movement and cell shape changes. Central to the process of cell fate determination in the ovary is the Drosophila epidermal growth factor receptor homolog (Egfr), which governs follicle cell fate decisions. In humans, Egfr is a member of the ErbB family of receptor tyrosine kinases, which control multiple cellular processes, including cell growth and differentiation.

Laura Nilson’s laboratory has used second-site modifier genetics to identify a new component in the pathway of Egfr signaling, called Capicua (Cic). Like Egfr, Cic is conserved in mammals but has not been studied in detail. The Nilson group is working out the mechanism and the potential intermediate molecules, by which Cic operates in tandem with Egfr.

Paul Lasko’s group concentrates on the Vasa protein, a germ cell specific translational regulator that accumulates at one end of the egg and regulates target RNAs that are essential for embryonic patterning and germ cell specification.

The Lasko group has discovered that Vasa interacts directly with a component of the general translational machinery to activate protein synthesis from gurken mRNA. gurken encodes an Egfr ligand of the transforming growth factor (TGF)-a family. The Lasko group has also biochemically isolated Vasa-containing molecular complexes, to identify partner proteins and other potential target mRNAs.

Work in Frieder Schöck’s lab concerns mechanisms of cell adhesion. In Norbert Perrimon’s lab at Harvard, he was instrumental in carrying out the first phenotype-based genome-scale RNA-interference screen in Drosophila tissue culture cells. By doing so, he has discovered several new genes whose functions are required for normal cell adhesion. He is continuing to characterize these genes to more fully understand their roles.

C. elegans:
a tool for drug discovery and for understanding cellular proliferation.

The study of the nematode Caenorhabditis elegans in the DBRI occurs from two major directions, one in which it is used as a tool for drug discovery, another in which it is used as a tool for understanding cellular proliferation and neural circuit development.

Siegfried Hekimi’s lab has been involved in using C. elegans to identify and study genes that affect physiological rates, including the rate of aging. The genes discovered by the Hekimi group are involved in modulating the production, detoxification or sensitivity to reactive oxygen species (ROS), toxic by-products of a variety of biochemical reactions. Their analysis strongly supports previous findings that ROS are at the heart of the aging process as well as some age-dependant diseases such as Parkinson’s and Alzheimer’s.

Joseph Dent’s laboratory uses C. elegans to understand how chemicals targeting the nervous system kill invertebrate pests and how invertebrates evolve resistance to these drugs. Specifically, the Dent group investigates how organisms become resistant to the antiparasitic drug ivermectin since nematodes, like pest insects, are both ivermectin-sensitive.

Richard Roy’s laboratory focuses on understanding how organisms develop in a precise and relatively invariant manner, and the ways in which developmental signals convey information to cells and thus control their ability to undergo division. In one instance, the Roy group focuses on the C. elegans intestine, formed from a single embryonic cell that undergoes mitotic divisions to produce all the cells that will give rise to the mature organ.  Using a genetic approach coupled with cell and molecular biological techniques, the group has identified mutants that affect cell division in the intestine, and are working to better understand both the tissue specificity of these mutants as well as why they cause cell cycle defects.

Monique Zetka’s laboratory investigates the molecular details of meiosis, and in particular is interested in the physical site at which genetic material is exchanged by homologous chromosomes during cell division. Many fundamental questions related to this process are still to be answered: how do homologous chromosomes recognize their partner? How does this recognition culminate in crossover events between them? What is the role of meiotic chromosome structure in mediating these events? The Zetka laboratory uses the tools afforded by the nematode system to investigate these processes and their relationship to one another.

Plant model systems:
Arabidopsis thaliana and Brassica napus.

Tamara Western’s laboratory uses the secretory cells, a particular cell type, of Arabidopsis thaliana as a model to study the processes and regulation of cell wall production and modification during plant development. Pectin is an integral component of plant cell walls, forming a gel-like matrix in which the cellulose microfibrils are embedded. The cell wall is vital for the structural integrity of cells and mediating interactions between cells and their environment; but little is known about the synthesis and transport of pectin to the cell wall or the regulation of these processes. Research on Arabidopsis has contributed to understandings of the molecular biology of eukaryotes in general.

Gregory Brown’s laboratory, also working on the cellular level, uses male sterile mutants of mitochondrial DNA that are affected in mitochondrial function to dissect the role of cellular energetics in the development of the Brassica napus flower. The male sterile phenotype of these mitochondrial mutants can be suppressed by dominant nuclear genes called restorers, that specifically down-regulate the expression of the mutant mitochondrial genes. Thus, the system is additionally useful for the study of the interactions between the nucleus and the mitochondria. The Brown group has made a significant advance in this area by being the first to isolate such a nuclear restorer gene in this species.

Expanding our frontiers:
applying our knowledge to vertebrate systems and to the evolution of developmental mechanisms.
While the DBRI’s primary focus will remain with invertebrate model organisms such as yeast, flies, and worms, have diversified our research interests to develop additional synergies.

François Fagotto’s laboratory uses the early amphibian embryo to study how intercellular signaling mechanisms function in the initial stages of development. The Wnt signaling pathway is involved in many developmental processes, as is the downstream component of this pathway,β-catenin. His work is conceptually very closely related to those of the Drosophila groups, but he adds complementary expertise in tissue separation and biochemical analysis to the developmental genetics that is the specialty of the fly groups.

If the genes that control embryonic development have been conserved throughout the animal kingdom, how have the same genes evolved over time to pattern diverse animal morphologies?

Ehab Abouheif’s laboratory addresses questions of animal differentiation over time through study of the expression of developmental genes both within and between closely related ant species. Studying how these genes are expressed in different castes in an ant colony, such as queens and workers, allows his group to study how these genes operate in different environmental conditions, and whether these environmental conditions play an important role in facilitating the evolution of genomes and morphology.