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? How external and internal signals control stress response and aging in animals? Finding answers to these major questions requires identification of key genes and understanding their expression and functional crosstalk. Since many such genes are also linked to diseases such as cancers, neuronal degeneration and premature death, a detailed knowledge of the regulatory networks of gene interactions and function will ultimately help develop treatments for major illnesses thereby improving human health and lifespan.
My group is investigating fundamental biological processes, e.g., cell signaling, cell proliferation, cell differentiation, and regulation of stress response, in two well-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 size (~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 genes that we have investigated for their role in reproductive system development is a LIM homeobox transcription factor LIN-11. Our findings have established that 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 (e.g., see Amon & Gupta, 2017).
More recently, we have collaborated with Dr. Chamberlin (Ohio State University, USA) to discover a new class of genes that inhibit cell proliferation (termed 'inappropriate vulva proliferation' or ivp). Our work (Chamberlin et al. 2019) has revealed that ivp genes encode novel, nuclear proteins that are important for chromatin-mediated gene regulation.
Another major focus of our lab is to investigate the mechanism of stress response and how it affects the behaviour and aging of animals.
We have found that an Axin family member in C. elegans, termed pry-1, plays an essential role in the maintenance of stress response and normal lifespan of animals. Axins are bona-fide components of Wnt signal transduction pathway (see this review). Mutations in Wnt signaling components lead to a variety of defects. As currently understood, Wnt proteins bind to receptors of the Frizzled and LRP families on the cell surface. Through Axin and several other cytoplasmic relay components, the signal is transduced to beta-Catenin, which enters the nucleus and interacts with TCF to regulate gene expression changes.
Interestingly, our work has suggested that PRY-1's role in aging does not involve any of the known factors of Wnt signaling. The data demonstrate that PRY-1 interacts with AAK-2 (AMP Kinase) and DAF-16 (FOXO family member), presumably in the form of a complex, to regulate genes involved in lifespan maintenance read the paper.
Our lab is also investigating the mechanism of electrotaxis behaviour in nematodes and its applications.
Electrotaxis is the movement of the organism in response to an electric field stimulus. In collaboration with Ravi Selvaganapathy (Mechanical Engineering, McMaster University) we provided the first evidence of electrotaxis response of C. elegans in a microfluidic device (Rezai et al., Lab Chip 2010). We demonstrated that worms, when exposed to a low voltage DC current inside a liquid-filled micro-channel, move in a directed manner towards cathode with a characteristic speed. This response is robust, instantaneous, and highly sensitive. Subsequently, we demonstrated that dopamine (DA) neurons play an important role in mediating the behavior. The involvement of DA signalling provides a basis to model Parkinson's disease in C. elegans, and to investigate the mechanism of neurodegeneration as well as to screen for chemicals with neuorprotective properties.