Mark A. Krasnow
Web: http://cmgm.stanford.edu/krasnow/
We are studying the molecular mechanisms of cell migration, cell adhesion, and tube formation during development of the Drosophila tracheal (respiratory) system. The tracheal system is a ramifying network of epithelial tubes that transports oxygen to the tissues, and it provides a tractable model for the development of related structures like the mammalian vascular system and lungs, which we have also begun to study. We use a combined in vivo and in vitro approach, employing genetic, cellular, and molecular methods to identify and characterize genes involved in the morphogenetic processes, and reconstruction of the processes in simplified in vitro systems to study the functions of the identified gene products.
There are 80 cells in each segment of the Drosophila tracheal system, and their behavior can be followed throughout development. Initially, the 80 cells form an epithelial sac, but soon small groups of cells migrate out from the sac in different directions and form primary branches. These then sprout secondary and ultimately terminal branches. During the sprouting process, several branches cease branching and fuse with branches from neighboring segments to interconnect the tubular network. Genetic screens have identified some 50 genes required for these cell migration and tube-formation and fusion events, and molecular characterization of the genes has begun to define the biochemical pathways in which they function. One of the key genes encodes a homolog of mammalian fibroblast growth factors (FGFs): the FGF guides the migration of tracheal cells during primary branch outgrowth by activating an FGF receptor, a transmembrane receptor tyrosine kinase, on the migrating tracheal cells. Other genes encode signal transduction components and we have begun to elucidate the signal transduction pathway to understand how FGF signaling controls cell migration and tube formation. We would also like to understand how the FGF pathway is modulated by factors like the secreted inhibitor Sprouty.
The fine terminal tracheal branches form by extension of long cytoplasmic processes from tracheal cells towards oxygen-starved tissues. This is regulated by a chemoattractant secreted by oxygen-starved tissues, which we recently found is the same FGF that guides outgrowth of the major tracheal branches earlier in developoment. However, during the later phase of development, expression of the FGF gene is induced by low oxygen. We wish to determine how cells sense when oxygen is limiting, and how this triggers increased expression of the FGF gene and the outgrowth of new terminal branches.
Manning, G. and Krasnow, M.A. (1993). Development of the Drosophila tracheal system. In The Development of Drosophila melanogaster (Eds. M. Bate and A. Martinez Arias), Cold Spring Harbor Press (Cold Spring Harbor, New York), pp. 609-685.
Samakovlis, C., Hacohen, N., Manning, G., Sutherland, D., Guillemin, K. and Krasnow, M.A. (1996). Development of the Drosophila tracheal system occurs by a series of morphologically distinct but genetically coupled branching events. Development 122, 1395-1407. (Medline)
Samakovlis, C., Manning, G., Steneberg, P., Hacohen, N., Cantera, R., and Krasnow, M.A. (1996) Genetic control of epithelial tube fusion during Drosophila tracheal development. Development 122:3531-3536. (Medline)
Sutherland, D., Samakovlis, C., and Krasnow, M.A. (1996) branchless encodes a Drosophila FGF homolog that controls tracheal cell migration and the pattern of branching. Cell 87, 1091-1101.
Guillemin, K. and Krasnow, M.A. (1997) The hypoxic response: Huffing and HIFing. Cell 89, 9-12.
Hacohen, N., Kramer, S. , Sutherland, D., Hiromi, Y, and Krasnow, M.A. (1998) sprouty encodes a novel antagonist of FGF signaling that patterns apical branching of the Drosophila airways. Cell 92, 253-263.
