Elucidating mechanistic connections between guidance signaling, microtubule regulation, and growth cone steering: Diversity Supplement

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Project Abstract It has long been established that growth cone navigation depends on regulated changes in both F-actin and microtubule (MT) dynamics in response to external guidance cues. However, the mechanisms by which these cues bring about specific changes in growth cone MT dynamics are a fundamental unresolved issue in the field. The parent research grant takes aim at that void, by investigating the functions of two interacting microtubule `plus-end tracking proteins' (+TIPs), TACC3 and XMAP215, and their regulatory mechanisms. These two +TIPs uniquely bind to the extreme end of the MT and their binding to MTs is thought to be regulated by phosphorylation. Our data support a model in which TACC3 and XMAP215 mediate changes in MT dynamics downstream of guidance cue signaling. We are currently funded to test the central mechanistic hypothesis that major guidance cue signaling pathways converge on TACC3 and XMAP215 to control MT plus-end dynamics and steer the growth cone. This supplement will fund the research training and career mentorship of a highly driven and enthusiastic first- generation female Hispanic undergraduate student, who has a strong interest and potential in eventually attending a graduate program in Biology. The undergraduate student will be trained not only in many diverse bench techniques, but she will be intensively mentored in how to be a successful biomedical scientist and succeed in a graduate PhD program in biology. With this supplement, she will work with a supportive team to make new insights into the mechanistic regulation of TACC3 during neural development, using a series of complementary approaches over the next three years. First, she will determine whether four critical phosphorylated amino acids are important for TACC3 biochemical interaction with XMAP215. Then, she will determine whether these amino acids affect the ability of TACC3 to bind to and regulate microtubules in neuronal growth cones. Finally, she will investigate whether these amino acids are important for TACC3 to promote normal swimming behaviors in Xenopus tadpoles as a readout of brain development. The undergraduate student will have extensive contact with her advisor as well as others on the parent grant (including a senior scientist, current PhD student, and senior undergraduate students). In the course of her undergraduate studies, she will have many opportunities to discuss and present her research in multiple forums, developing her skills not only as a bench biomedical researcher but as a scientific communicator. She will receive intensive mentoring from her advisor, and will participate in numerous additional training opportunities to strongly prepare her for the rigors of a graduate program.