About Dr. Dubreuil's Research

Animals generate a remarkable diversity of different cell types ranging from the polygonal epithelial cells that compartmentalize our bodies to the long thin neurons that form electrical connections from brain to muscle. Every generation all of this diversity has to be generated de novo from a starting population of stem cells in the early embryo. Yet, as different as cell types can be, within any particular cell type there is relatively little variation. A given nerve or epithelial cell type has constant dimensions within a tissue or between the same tissues from any two individuals. What are the developmental programs and molecular mechanisms that explain this regularity in cell form?

My laboratory studies these questions using the fruit fly as a model system in which powerful genetic tools can be used to dissect cell structure and function. Much of our work has been focused on the protein spectrin which forms a protein scaffold beneath the plasma membrane in many different cell types. Defects in the spectrin scaffold are known to cause a variety of human diseases ranging from anemia to neurodegeneration to cardiac arrhythmia and muscular dystrophy. Understanding the basic biology of spectrin and its relatives is therefore critical to understanding these human disease processes. Several models proposed over the years invoke spectrin as a critical mediator of cellular morphogenesis.

Our work over the past few years has produced a number of suprising new insights into the assembly and function of spectrin. First, the proposed rules for spectrin assembly in vertebrate cells do not appear to apply in Drosophila. We are exploring the possibility that studies in vertebrates have missed an important facet of spectrin biology. Second, a number of mutant spectrin alleles that we have characterized affect growth of the organism, presumably by affecting cell growth. This is one of the few clearcut phenotypes that we observe in Drosophila spectrin mutants. Otherwise, much of early development and cellular morphogenesis is relatively normal in the virtual absence of spectrin. We are testing the possibility that the lethality of loss-of-function spectrin mutations stems from this effect on growth.

A third area of current research grew out of our interest in the biology of the gut epithelium in Drosophila. As in many other invertebrates, the digestive tract of Drosophila larvae is lined with a specialized extracellular matrix (known as the Peritrophic Membrane or PM). The PM is somewhat like a sausage casing that is continually secreted at the anterior end of the gut and moves like a conveyor carrying food and ultimately waste through the organism. It is impervious to almost everything we can feed to larvae, supporting its suggested function as a barrier against infection and mechanical damage to the epithelium. Secretion of the PM is intriguing from the standpoint of epithelial biology and also digestive physiology. Somehow nutrients and digestive enzymes must efficiently pass through this formidable barrier. The development of ways to breach the PM barrier is likely to have useful implications for the development of new insecticides and will also improve our understanding of disease agents such as malaria and sleeping sickness which have already figured out a way to get through.

Representative Publications

A. Das and R. R. Dubreuil (2009) Spectrin: Organization and function in neurons. In Encyclopedia of Neuroscience (LR Squire et al, eds), Elsevier Ltd, pp. 213-218.

A. Das, C. Base, D. Manna,W. Cho, R.R.Dubreuil (2008) Unexpected complexity in the mechanisms that target assembly of the spectrin cytoskeleton. J. Biol. Chem. 283:12643-12653.

D.S. Garbe, A. Das, R.R. Dubreuil, G.J. Bashaw (2007) Alpha and beta spectrin function independently of ankyrin to regulate the establishment and maintenance of axon connections in the Drosophila embryonic CNS. Development 134:273-284.

R. R. Dubreuil (2006) Functional links between membrane transport and the spectrin cytoskeleton. J. Membrane Biology. 211:151-161.

R.R. Dubreuil (2006) Spectrin function: A survey of genetic systems from Drosophila to humans. In: Advances in Molecular and Cell Biology, Vol. 37. Aspects of the Cytoskeleton (S. Khurana, editor).

A. Das, C. Base, S. Dhulipala, R.R. Dubreuil (2006) Spectrin functions upsteam of ankyrin in a spectrin cytoskeleton assembly pathway. J. Cell Biol. 175:325-335.

R.R. Dubreuil (2004) Copper cells and stomach acid secretion in the Drosophila midgut. Int. J. Biochem & Cell Biology. 36:742-752.