The microtubule cytoskeleton is required for multiple essential functions of the cell, including vesicle transport, organelle positioning, cell migration and assembly of the mitotic spindle. The centrosome acts as the primary organizer of the cytoskeleton, regulating microtubule nucleation, growth, and positioning. Human diseases such as autosomal recessive primary microcephaly are primarily caused by defects in proteins that are localized to, and function at, the centrosome1. As such, developing an understanding of how these proteins act at the centrosome to promote cytoskeletal organization is also of medical relevance. Hundreds of proteins have been identified as components of the centrosome2,3, yet how specific proteins act to promote new microtubule nucleation from the cell's dominant microtubule organizing center is still unknown. Despite identification of the gamma-tubulin ring complex (?-TuRC) as a major microtubule nucleator in the cell4-7, it remains unclear how it gets localized and activated specifically at the centrosome to generate microtubules. The overall goal of this proposal is to determine how the centrosome nucleates microtubules for building the microtubule cytoskeleton of the cell. In order to achieve this goal, I will develop an assay to visualize, in real time, new microtubule formation at the centrosome in a cell-free system using single molecule microscopy. I will investigate which proteins are responsible for localizing ?-TuRC to the centrosome and for specifically activating it there. Finally, I will determine how the key molecular players induce centrosomal microtubule nucleation. Completion of these aims will provide a molecular understanding of how microtubules are nucleated at the centrosome and how this contributes to building the microtubule cytoskeleton in health and disease.

Public Health Relevance

Microtubules organized by the centrosome form the cytoskeleton of the cell and are required for essential cell functions such as cell division and organelle positioning. Disruption or misregulation of centrosome function can have wide-ranging effects on human health, including cancer, microcephaly and dwarfism. The experiments described in this proposal will characterize the function of a number of proteins involved in building the microtubule cytoskeleton from the centrosome, and as such, will provide insight into appropriate treatments for diseases caused by centrosome dysfunction.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1)
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Sakalian, Michael
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Princeton University
Schools of Arts and Sciences
United States
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Rale, Michael J; Kadzik, Rachel S; Petry, Sabine (2018) Phase Transitioning the Centrosome into a Microtubule Nucleator. Biochemistry 57:30-37
Thawani, Akanksha; Kadzik, Rachel S; Petry, Sabine (2018) XMAP215 is a microtubule nucleation factor that functions synergistically with the ?-tubulin ring complex. Nat Cell Biol 20:575-585
Song, Jae-Geun; King, Matthew R; Zhang, Rui et al. (2018) Mechanism of how augmin directly targets the ?-tubulin ring complex to microtubules. J Cell Biol 217:2417-2428
Ducker, Gregory S; Chen, Li; Morscher, Raphael J et al. (2016) Reversal of Cytosolic One-Carbon Flux Compensates for Loss of the Mitochondrial Folate Pathway. Cell Metab 24:640-641