Mini Jose DeepakRamalingaswami and IYBA Faculty Fellow
Phone : +91 80 2293 2518
E-Mail : mini[at]iisc.ac.in
Differentiation of neuronal processes into subtypes
How do neurons differentiate?
Establishment of cell polarity plays a crucial role for development, motility and survival in all eukaryotic systems. Diffusion of biomolecules on the plasma membrane creates asymmetry, generating cell polarity. Lipid homeostasis plays a major role in creating this molecular asymmetry. My group focuses on addressing a fundamental, yet important question in neuroscience: How is cell polarity established during neuronal development or how do the neurons differentiate?
Differentiation of neuronal processes into subtypes namely, axons and dendrites, remain to be a highly intriguing but critical mechanism for survival during neuronal development. It plays a key role in establishing specialized neuronal processes to form cell-cell contacts or synapses, crucial for signal processing in the brain. Early in development, the short neuronal processes called neurites grow similar to each other in a symmetric manner. A sharp transition during the growth period allows one of the processes to grow at a much faster rate compared to the other processes, which develops as the axon. It has been found that there are molecular and structural differences between axons and the dendrites. Interestingly, though different approaches have been adopted to intercept the molecular mechanism behind, a clear model on this critical transition during development, which determines neuronal survival, remains to be understood.
Lipid metabolism has been shown to hold the key to major fundamental processes including neuronal differentiation. In my lab, we try to unravel the molecular mechanisms underlying neuronal polarity using a multidisciplinary approach combining molecular biology, genetic engineering, pharmacology, Optogenetics and multiple advanced microscopy paradigms including FRET, FLIM and single molecule based superresolution microscopy. A combination of state-of-the-art interdisciplinary paradigms is adopted to understand the collective spatiotemporal events resulting in complex neuronal structure and function using rodent hippocampal neurons as a model system.
Recent evidence from our lab is one of the first which signifies the stark effect of a transient alteration in membrane resulting in altered membrane viscosity and Brownian diffusion, thereby resulting in long term deficits in neurite outgrowth and polarity establishment (Jose et al, Front. Mol. Neur. 2021). Our study also emphasizes the importance of addressing this condition at an early developmental phase, when the deficits can be rescued by precise control of the membrane lipid balance. Thus, this study identified membrane cholesterol as a critical factor for axo-dendritic specification and a key molecule for determining neuronal architecture.
Combining optogenetics with super resolution microscopy, we showed how photoactivation controls the stochastic organization and lateral random movement of single molecules of HCN channels, crucial in regulating the membrane potential, in live cells by altering the intracellular cAMP levels (Tanwar et al, RSC Chem. Bio., 2021). This study shows one of the first paradigms combining these state-of-the-art techniques to alter the biochemical maps of ion channels in live cells. Our current studies focus on understanding the correlation of these pathways and their implication in multiple developmental and neurodegenerative disorders.