Defining the Roles of the Microtubule-Associated Protein TACC in Drosophila Synapse Development

Drosophila melanogaster;microtubules;synapse;transforming acidic coiled coil protein;active zone

Chou, Vivian T. ; Kaeser, Pascal

University:Havard University

Department:Medical Sciences

关键词: Drosophila melanogaster;    microtubules;    synapse;    transforming acidic coiled coil protein;    active zone;   

Others  :  https://dash.harvard.edu/bitstream/handle/1/37365933/CHOU-DISSERTATION-2020.pdf?sequence=1&isAllowed=n

美国|英语

来源: Digital Access to Scholarship at Harvard

【 摘 要 】

The development of the synapse, the essential functional unit of the nervous system, is a highly regulated process underlying neuronal circuitry and plasticity. Following axon pathfinding, complex signaling networks coordinate development of precise connections between pre- and postsynaptic compartments to establish a stable junction. Among the major effectors of these signaling networks are the actin and microtubule (MT) cytoskeletons. Despite comprehensive studies of the neuronal cytoskeleton in the postsynaptic context, a molecular understanding of the presynaptic cytoskeleton is still developing, and presynaptic MTs remain particularly enigmatic. Pioneering studies at the Drosophila neuromuscular junction (NMJ) have revealed critical roles for several MT-associated proteins (MAPs); however, many outstanding questions remain, such as how MT assembly/stabilization are coupled to morphological changes, and the potential significance of plus-end dynamic instability at the synapse.In my dissertation research, I have aimed to address these questions through studies of the MAP dTACC, a novel regulator of synaptogenesis in Drosophila. TACC-family proteins are primarily known for regulating spindle MTs in mitotic cells, but have also been studied in interphase systems, including non-synaptic neurons. Here, I report that presynaptic dTACC is a negative regulator of bouton addition, and therefore synapse expansion. Consistent with known roles, dTACC localizes to the presynaptic MT lattice and is required to maintain the integrity of higher-order MT architecture in motor axon terminals. I furthermore describe the development of a live-imaging and automated analysis strategy to investigate the effect of dTACC on synaptic MT dynamics, and the resultant finding that dTACC regulates both pre- and postsynaptic plus-end dynamics. This is consistent with previously described roles for dTACC and moreover raises the possibility that dTACC acts as a plus-end tracking protein (+TIP) at the synapse. Taken together, these findings support a model of synaptogenesis where a precise equilibrium of NMJ expansion and restriction is modulated by changes to the underlying cytoskeleton, which is under the control of a complex network of MAPs and other factors. Future research will focus on elucidating the biochemical mechanisms underlying the function of synaptic dTACC as well as the roles of dTACC in the postsynaptic compartment.