Sir Henry Dale Fellow
Dhanya Cheerambathur is a Sir Henry Dale Fellow at the Wellcome Centre for Biology. Her group is interested in molecular mechanisms that establish the microtubule cytoskeleton during neuronal development. To study this process, her lab uses a combinatorial approach involving genetics, high time resolution microscopy and biochemical approaches employing C. elegans as the primary model organism. Dhanya obtained her PhD in Cell and Developmental Biology from University of California, Davis in the lab of Jonathan Scholey and later moved to University of California, San Diego to pursue her postdoctoral studies with Arshad Desai. She has been at the University of Edinburgh since May 2018.
Role of microtubule cytoskeleton in building and regenerating the neural connectome
The central nervous system is a complex network of neurons and supporting cells that form the information relaying unit of an organism. During neural development, pioneer neurons extend axons in response to guidance cues from other neurons and non-neuronal cells to establish the framework that build the neural circuits. The assembly of this circuit is a highly orchestrated event that involves neurite outgrowth, fasciculation (axon bundling) and synapse formation to generate a functional nervous system. How these organizational features emerge during development is poorly understood.
Microtubules are critical for neuron formation and function. As neurons develop, microtubules are organized and sculpted by the cell machinery to form the axons, dendrites and the neural network. Several human neurodevelopmental disorders are linked to mutations in microtubule cytoskeleton-related proteins. Despite the central role of the microtubule, little is known about how the microtubule cytoskeleton contributes to the assembly of the neural circuit. We aim to understand how the microtubule cytoskeleton uses distinct molecular machinery to build and regenerate 3 dimensional neuronal circuits using the simple multicellular organism C. elegans as a model.
During my post-doc, I discovered an unexpected role for kinetochore, the chromosome segregation machinery, in developing neurons of C. elegans. Our work showed that the evolutionarily conserved 10 subunit KMN (Knl1-Mis12-Ndc80) network, the microtubule coupler within the kinetochore, acts post-mitotically in developing neurons. A similar function for kinetochores proteins has also been described in Drosophila and rat hippocampal cultures. KMN proteins are enriched in the dendritic and axonal outgrowth during neurodevelopment. Removal of KMN components post-mitotically from developing neurons resulted in a disorganized nerve ring, a network of 181 axons and synapses, considered as the “brain” of C. elegans. We hypothesize that the kinetochore proteins facilitate nerve ring assembly by promoting the proper formation of axon bundles.
Starting from this unique angle, we aim to understand how the microtubule cytoskeleton integrates distinct molecular machinery to build and regenerate 3 dimensional neuronal circuits in C. elegans. Our goal is to 1) define the function of the kinetochore proteins in building the nerve ring; 2) build a functional map of microtubule cytoskeleton during nerve ring assembly by addressing the function of non-kinetochore microtubule factors; 3) investigate how kinetochore proteins build and maintain neuronal network by addressing its role in dendritic branching and regeneration.
Cheerambathur, D.K., Prevo, B., Chow, T.-L., Hattersley, N., Wang, S., Zhao, Z., Kim, T., Gerson-Gurwitz, A., Oegema, K., Green, R., et al. (2019). The Kinetochore-Microtubule Coupling Machinery Is Repurposed in Sensory Nervous System Morphogenesis. Dev. Cell.
Cheerambathur, D.K., Prevo, B., Hattersley, N., Lewellyn, L., Corbett, K.D., Oegema, K., and Desai, A. (2017). Dephosphorylation of the Ndc80 Tail Stabilizes Kinetochore-Microtubule Attachments via the Ska Complex. Dev. Cell 41, 424–437.e424.
Cheerambathur, D.K., Gassmann, R., Cook, B., Oegema, K., and Desai, A. (2013). Crosstalk between microtubule attachment complexes ensures accurate chromosome segregation. Science 342, 1239–1242.
Nerve ring assembly in C.elegans
A. The C.elegans head nervous system in L1 larvae (PH marks the membrane and histone the cell body). The axon bundle in the nerve ring is between white arrowheads (scale 10 mm).
B. Schematic of KMN network: Mis-12 interface (red) with the centromere, Ndc80 (purple) binds the microtubule and Knl1 (blue) functions as a scaffold.
C. Structure of C.elegans nerve ring in control and after post-mitotic degradation of KNL-1 in the neurons. Axon defasciculation defect (white arrowhead, scale 5 mm).
D. Fluorescence image and cartoon of the developing nerve ring in C.elegans embryo (pioneer neurons (PN) in purple, amphid sensory neurons (ASN) in blue). Note that the ASNs have already extended their dendrites (scale 2.5 mm).
E. Schematic representing the initial stages of nerve ring formation. Insets show the extension and bridging of bilaterally symmetrical PN axons (scale 1 mm).