How cells form tissues? How do they communicate with each other and respond to environmental signals? How cell-cell interactions give rise to complex animal behavior? Finding answers to these major questions requires identification of key genes and understanding their expression and functional crosstalk. Since such genes are also linked to diseases such as cancers and neuronal degeneration, a detailed knowledge of the regulatory networks of gene interactions and function will ultimately help develop treatments for major illnesses thereby improving human health.
My group is investigating three fundamental biological processes, namely, cell signaling, cell proliferation, and cell differentiation, in two established animal models, C. elegans and C. briggsae. These two nematode species (or worms) offer many experimental advantages including rapid development (~3 days from egg to adult), transparency, small (~1 mm), hermaphroditic life style, and compact genome (~100 megabases). Approximately two-thirds of the genes in worms have human homologs and many of the gene function and cellular and molecular processes are conserved all the way to human.
Major areas of research in our lab focus on:
A major part of our research focuses on the reproductive system, specifically the vulva, an organ that serves as a passageway for mating and laying eggs. In C. elegans vulva is formed by the progeny of three out of six multipotential vulval precursor cells (VPCs) that divide three times to give rise to twenty-two cells. The vulval progeny differentiate during L4 larval stage to generate seven different cell types leading to the formation of an adult vulva. The invariant lineage of the VPCs and stereotypic positions of their progeny offer experimental analyses at single-cell resolution.
One of the projects involves investigating the regulation and function of a LIM homeobox transcription factor LIN-11. LIN-11 is a key regulator of vulval morphogenesis. In lin-11 mutant animals, vulval cells fail to acquire correct identities and inappropriately fuse with each other (Gupta et.al, 2003). Thus, lin-11 confers cell identity by regulating the expression of cell type-specific genes. We are taking a variety of approaches in Genetics, Molecular Biology and Bioinformatics to understand the molecular basis of lin-11 regulation and its downstream targets during vulval morphogenesis.
Another project deals with the regulation of Wnt Signal transduction pathway. Wnt proteins form a family of highly conserved secreted signaling molecules that regulate cell-to-cell interactions during embryogenesis. Insights into the mechanisms of Wnt action have emerged from several systems: genetics in Drosophila and C. elegans; biochemistry in cell culture and ectopic gene expression in Xenopus embryos. Mutations in Wnt genes or Wnt pathway components lead to specific developmental defects, while various human diseases, including cancer, are caused by abnormal Wnt signaling. As currently understood, Wnt proteins bind to receptors of the Frizzled and LRP families on the cell surface. Through several cytoplasmic relay components, the signal is transduced to beta-catenin, which enters the nucleus and forms a complex with TCF to activate transcription of Wnt target genes.
Our lab is also investigating the electrotaxis phenomenon in nematodes, the neuronal basis of this behavior, and its applications.
Electrotaxis is the movement of organisms in response to an electric field stimulus. In collaboration with Ravi Selvaganapathy (Mechanical Engineering, McMaster University) we provided the first evidence of electrotaxis in C. elegans in a microfluidic channel environment (Rezai et al., Lab Chip 2010). We showed that low voltage DC electric field induces worms to swim towards cathode with a characteristic speed. This response is robust, instantaneous and highly sensitive. Subsequently, we demonstrated that dopamine (DA) neurons play important role in mediating the electrotaxis behavior. The involvement of DA signalling provides a basis to model Parkinson's disease in C. elegans, and to investigate the mechanism of neurodegeneration and to identify neuorprotective chemicals.