Neurons are highly polarized cells whose structure and function are intimately tied to their microtubule cytoskeleton. As a neuronal precursor transforms into a mature neuron, distinct functional domains emanate from their cell bodies — the axon and the dendrite. This process involves the reshaping of a radial microtubule array in a neuronal precursor into parallel microtubule array of uniform polarity in axons and mixed polarity in dendrites. Distinct microtubule-associated proteins regulate microtubule organization and function in neurons, and mutations in these proteins are linked to human neurodevelopmental disorders. However, the molecular mechanisms that build the unique microtubule architecture in a developing neuron are poorly understood.
Neuronal differentiation is tightly linked to cytoskeletal reorganization.
The overarching goal of our research is to gain a detailed mechanistic understanding about how neuronal cells assemble and maintain their complex microtubule architecture. We are particularly interested in deciphering how various microtubule regulators contribute to this process. The lab employs a multidisciplinary approach involving classical genetic methods and state of the art genome editing tools (CRISPR), and high temporal imaging of neuronal development in vivo in C. elegans to manipulate and visualize the dynamic cellular structures within the neuron.
1. Function of kinetochore proteins during neuronal development
Recently, we discovered that components of the kinetochore, the ancient and conserved microtubule-coupling machinery that segregates chromosomes, are redeployed during neuronal development. Specifically, we found that the evolutionarily conserved 10-subunit KMN network (KMN: Knl1 complex/Mis12 complex/Ndc80 complex), which acts as a dynamic coupler between mitotic chromosomes and spindle microtubules in dividing cells, is important for initial dendritic extension, a critical early step in the establishment of the sensory nervous system.
Post-mitotic degradation of KMN-components impairs initial dendritic extension.
Our current efforts are focused on elucidating the molecular mechanism by which kinetochore proteins contribute to microtubule organization and function within the neurons.
2. Role of microtubule regulators during neuronal development
Microtubule assembly and organisation in developing neurons likely requires diverse set of microtubule associated proteins. These include microtubule nucleator like gamma tubulin, end associated proteins such as EB1 and Patronin and other microtubule associated proteins like CENP F and doublecortin which are linked to neurodevelopmental disorders. Many of these components are also known to have roles during cell division. However, defining their roles in neuronal development has been hindered by a lack of tools to bypass their mitotic function, as well as lack of an in vivo system amenable to visualization of underlying cellular and structural dynamics. A key focus of the lab is to tease apart the functions of these diverse regulators during neuronal morphogenesis.
Microtubule organization and dynamics in the C. elegans embryo.