Dynamic architecture and function of microtubule networks

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Summary Microtubules (MTs) are dynamic biopolymers, which serve as major highways for intracellular transport. MT networks are critical for cell physiology, and their disturbance underlies many human diseases. My laboratory studies global mechanisms allowing MTs to perfectly attribute to specific cellular functions. MT-dependent transport arranges multiple cell components at the same time. To address these complex requirements, MT geometry, molecular motor affinity, and/or MT association with to other cell components are tightly regulated. MT network geometry changes depending on the sites of new MT outgrowth (the MT-organizing centers, or MTOCs), local stabilization/disassembly of MTs, and MT anchoring to other structures. Furthermore, the affinity of individual MTs to molecular motors can be modulated to affect intracellular transport. Finally, MTs can scaffold proteins or be cross-linked with other cytoskeletal components. All those mechanisms that tailor MT organization to distinct cell functions can respond dynamically to cell-signaling inputs and the physiological context. Together, molecular regulation and functional specialization of MT networks comprise a global field in basic cell biology with numerous unanswered questions. My research program’s long-term goals include defining: how interphase MT networks are built and regulated; specific mechanisms tailoring MT biochemistry and geometry to specific cellular needs; the methods whereby MTs collaborate with other cellular systems to build intracellular space; and, how MTs switch their functional loads between distinct tasks to arrange integral cell architecture under changing signaling conditions. Since April 2018, the NIGMS MIRA funding mechanism has been an invaluable resource allowing us to explore these basic, fundamental biological problems. We have published several central advances toward our global and interactive goals. Among other findings, we brought a new mechanistic understanding of Golgi-derived MT networks (GDMTs, which were identified in our prior studies); described novel, surprising functions for MT- associated proteins (MAPs) tau, CLASP2, and CAMSAP2; utilized collaborations with experts in computational modeling for deep understanding of MT functions in secretory trafficking and actin cytoskeleton dynamics; and, discovered a previously overlooked, physiologically important Golgi complex behavior in the cell cycle. In the next five years, I will extend mechanistic and functional insights in two broad directions of my program’s extant NIGMS-funded research. (I) We will determine how the versatility of MT functions is tuned by multifunctional MAPs, focusing on (a) secretory trafficking through the Golgi axis and (b) the organization of the actin cytoskeleton. Initial studies will evaluate the roles of MT regulators CLASPs and a MT-stabilizing tumor suppressor RASSF1A. (II) We will expand our studies of MT-dependent Golgi positioning to dissect (a) molecular mechanisms driving this process and (b) the significance of Golgi relocation in distinct cell cycle stages.