Research
Clathrin in Development and Disease
Clathrin in Development
Our previous work has demonstrated that clathrin mediated endocytosis (CME) is critical for the maintenance of pluripotency of embryonic stem cells. Through CME, a balance in the levels of E-cadherin and signaling downstream of TGF-beta is maintained in embryonic stem cells. Any alteration in CME results in an imbalance, causing an exit from the pluripotent state (Narayana et al., 2019, Stem Cell Reports).
Clathrin in development:
We further demonstrated that the loss of CME in embryonic stem cells results in an alteration in their physical properties, which are largely driven by changes in the organization of the actin cytoskeleton (Mote et al, 2020, Journal of Biological Chemistry)
We attempted to understand the role of individual clathrin light chains in the context of mammalian development using genetically modified embryonic stem cells and cell lines. Our results demonstrated that clathrin light chain a specifically regulates the organization of the actin cytoskeleton and the secretion of the Wnt ligand (Tiwari et al, 2025, Life Science Alliance)
Our current research is aimed at understanding the function of individual clathrin light chains in regulating organellar function and cytoskeletal organization.
Clathrin in Disease
Huntington’s disorder is a neurodegenerative disorder characterized by the expansion of CAG repeats (encoding the amino acid Glutamine) in the Huntingtin gene of patients. Proteins carrying an abnormal number of repeats form aggregates, eventually resulting in severe neurodegeneration. Using Drosophila melanogaster as a model system, we demonstrated that clathrin-mediated endocytosis and other features of intracellular trafficking are severely affected in cells containing Huntingtin aggregates. The defect in CME was caused by alterations in the organization of the actin cytoskeleton. Overexpression of specific actin organizing proteins were capable of alleviating these effects, thus providing a unique potential to develop therapies for Huntingtin’s disorder (Singh et al., 2024, eLife)
Recent clinical studies have established the presence of mutations in the gene encoding for clathrin heavy chain (CLTC) in human patients diagnosed with intellectual disability. However, the exact molecular role of such mutations is poorly understood. The clathrin heavy chain is highly conserved through evolution. We therefore used mammalian cells and transgenic Drosophila lines to understand the effect of pathogenic mutations. Our results demonstrate that these mutations affect trafficking in cells and impair neurodevelopment, learning and memory in Drosophila models (Das et al, iScience, 2026)
We are currently trying to understand the mechanisms by which pathogenic mutations in the clathrin heavy chain result in intellectual disability and developmental delay.
Funding Sourcess
