Introduction – A fundamental event in neuronal morphogenesis is the establishment of neurites that develop into morphologically and functionally distinct domains of a neuron, the dendrite and axon. It is well known that this process involves dynamic remodelling of the microtubule cytoskeleton whereby a radial microtubule array in a neuronal precursor reshapes, acquiring uniform polarity in axons and mixed polarity in dendrites. However, the precise function of the microtubule cytoskeleton as well as the molecular mechanism behind neurite establishment is poorly understood. Several classes of microtubule-associated proteins are known to function during neuronal development and many are mutated in neurodevelopmental disorders. Understanding how the function of the different microtubule regulators is spatially and temporally coupled to the neuronal differentiation program is imperative to determine how developing neurons generate the distinct local subpopulations of microtubule arrays.
Project – Molecular mechanism involved in building the neuronal microtubule cytoskeleton | Dr Dhanya Cheerambathur
School of Biological Sciences | PhD Research Project – Competition Funded – Students Worldwide | Application Deadline: N/A
Project – Distinct microtubule-associated proteins regulate microtubule function in neurons, and mutations in these proteins are linked to several human neurodevelopmental disorders. However, it is not well understood how the different microtubule regulators build the unique neuronal microtubule architecture and how mutations in them manifest in the disease state of neuron. The goal of this project is to understand the role of kinetochore machinery in neuronal development in C. elegans and mammalian cell culture systems.
The PhD student will investigate:
a) How does kinetochore machinery contribute to neuronal microtubule organization?
b) The identity of subcellular structures associated with the kinetochore proteins in neurons.
Overall the student will learn state-of-the-art in vivo high-resolution live cell microscopy, biochemistry, genetics (e.g. CRISPR based genome edits) and molecular biology techniques. The student will engineer and develop visualization tools (e.g. microtubule, membrane and neuronal cell specific markers) to assess the morphological and cytoskeletal changes associated with neuronal development. These tools will then be used in conjunction with genetic approaches (e.g. loss of function alleles & knockouts) to determine the functions of kinetochore proteins in neuron. The student will also be trained various image analysis tools (e.g. Image J). Taken together, the student will develop experience in quantitative cell biology using the latest genetic and imaging tools to tackle questions related to neuronal development.
If you have any further questions please feel free to contact me!
1. Cheerambathur, D.K., Prevo, B., Chow, T., Hattersley, N., Wang, S., Zhao, Z., Kim, T., Gerson-Gurwitz, A., Oegema, K., Green, R. and Desai, A. (2019). The kinetochore-microtubule coupling machinery is repurposed in sensory nervous system morphogenesis. Developmental Cell 48.
2. 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.
3. Cheerambathur, D.K., Prevo, B., Corbett, K.D., Oegema, K. and Desai, A. (2017). Phosphorylation of the Ndc80 tail stabilizes kinetochore-microtubule attachments via the Ska complex. Developmental Cell 41: 424-437.
4. Tas, R.P., and Kapitein, L.C. (2018). Exploring cytoskeletal diversity in neurons. Science 361, 231–232.