Summary: Using the fruitfly Drosophila melanogaster as a model system, we are addressing two fundamental questions in biology: (i) What is the mechanism by which the various cells/tissues/organs are positioned in their respective places in our body? (ii) How are shape and size of different organs determined? Not only that our group has identified key mechanisms that specify organ development and regulate growth control in Drosophila, we have also expanded our study by including human clinical samples to examine the status of these evolutionarily conserved mechanisms in various epithelial cancers.
The fruitfly Drosophila melanogaster is one of the most studied genetic systems. Many genetic pathways have been well characterized in this organism and it is accessible to a variety of genetic manipulations. Not only that a large number of genes are highly conserved between flies and human, several developmental events, pathways, cell and tissue organization etc are similar between the two systems. Using Drosophila as a model system, we are addressing two fundamental questions in biology: What is the mechanism by which various cells/tissues/organs are positioned in their respective places in our body? How are shape and size of different organs determined? Our approach to address these questions is studying molecular and morphogenic events downstream to Hox genes, which play critical roles in the elaboration of segmental identities along the antero-posterior axis in all bilaterian animals.
In Drosophila, wings and halteres are the dorsal appendages of the second and third thoracic segments, respectively. In the third thoracic segment, wing development is suppressed by the Hox gene Ultrabithorax (Ubx) to mediate haltere development (Lewis, 1978). Loss of Ubx function from developing haltere discs induces haltere-to-wing transformations, whereas ectopic expression of Ubx in developing wing discs leads to wing-to-haltere transformations (Lewis, 1978). Thus, the differential development of wings and halteres constitutes a good genetic system to study cell fate determination at different levels such as growth, cell shape, size and its biochemical and physiological properties. They also represent the evolutionary trend that has established the differences between fore and hind wings in insects, wings and legs in birds and fore and hind limbs in mammals.
One way to approach the mechanism of Ubx function is to reconstruct a wing appendage in the third thoracic segment without altering the patterns/levels of Ubx expression. This necessitates identification of genes that are differentially expressed between wing and haltere during development and reverse-engineer the expression of one or more of those genes during haltere development. We have employed two complementary approaches in our studies, the first one being the examination of genetic interactions between Ubx and certain other genes that are already shown to be functional during wing and haltere development and the second approach is identification of downstream targets of Ubx function by highthroughput techniques such as microarray and ChIP-chip (more recently RNA-Seq and ChIP-seq).
Results from our lab suggest that Ubx down regulates activities of the signaling centers, such as anterior-posterior (A/P) and dorso-ventral (D/V) organizers, to specify haltere fate. Our observations also suggest a mechanism by which Ubx dampens organizing activities of compartment boundaries and thereby, represses the wing fate. Our work has, thus, opened up new avenues to study genetic mechanisms that help fine-tuning signal transduction pathways. We have demonstrated that differential development of wing and haltere discs is a good assay system to identify, hitherto unknown, regulators or mechanism of regulation of key signal transduction pathways, such as Wnt, Hedgehog, Notch, TGF-b and Egfr/Ras pathways, which are implicated in many cancers.
Our current and future efforts in this direction are to understand molecular changes that are associated with the evolution of halteres in Dipterans such as Drosophila. This involves extensive bioinformatics analyses and identifying direct targets of Ubx from different insect groups such as Apis, butterflies, silkworm, Tribolium, mosquito and different species of Drosophila.
Our current and future work also involves functional genomics using Drosophila as a genetic system to study human genes and to develop fly models of human diseases. In this direction, (i) we are investigating the function of dA2BP1, the Drosophila orthologue of human Ataxin-2 binding protein 1, which is implicated in Spinocerebellar Ataxia type 2 and (ii) we have initiative a large genetic screen to identify context-specific inhibitors of growth in epithelial tissues. Orthologues of may of these inhibitors in human are well-known tumor suppressors opening up ways to identify additional such proteins and perhaps, markers for better diagnosis and prognosis.