The long-term goals of this proposal are to understand the regulatory mechanisms that allow organelle transport to be integrated with development. Motor-driven transport along microtubules plays many essential cellular roles, yet the mechanisms with which cells control its specificity, timing and destination remain a mystery. A newly developed model system, lipid-droplet motion in Drosophila embryos, provides the opportunity to attack this long-standing problem in cell biology with an interdisciplinary approach utilizing genetic, biophysical, and molecular techniques. 1) Experiments are proposed to establish how the Halo protein, a novel trans-acting regulator, mediates developmental transitions in droplet transport. The temporal expression and intracellular localization of Halo will be monitored to test whether Halo is the signal that determines timing and directionality of transport and whether Halo physically associates with motors on droplets. A structure-function analysis will be employed to generate models about Halo's biochemical activity. Nanometer-scale tracking and stall-force measurements with optical tweezers in wild-type and mutant embryos will determine at the single-organelle level which physical parameters of motion Halo controls. 2) To identify additional determinants of transport directionality, new mutations altering net droplet transport will be isolated. The genes defined by these mutations will be molecularly cloned, and their physical and functional interactions with known components of the droplet transport machinery will be established. Genes also important for other transport pathways will be preferentially analyzed to define key general regulators of organelle motility. 3) To investigate how organelle-specificity of transport is established, the targeting of cytoplasmic dynein to several embryonic cargoes will be compared. In particular, the hypothesis will be tested that different isoforms of the intermediate chain of cytoplasmic dynein recruit the motor to yolk vesicles, lipid droplets, and mitochondria. Understanding how microtubule motors are controlled has broad significance for human health since aberrant motor function has been linked to diseases ranging from birth defects to cancer, schizophrenia and Alzheimer's disease.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Special Emphasis Panel (ZRG1-CDF-4 (02))
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Rodewald, Richard D
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Brandeis University
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Arora, Gurpreet K; Tran, Susan L; Rizzo, Nicholas et al. (2016) Temporal control of bidirectional lipid-droplet motion in Drosophila depends on the ratio of kinesin-1 and its co-factor Halo. J Cell Sci 129:1416-28
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Elhanany-Tamir, Hadas; Yu, Yanxun V; Shnayder, Miri et al. (2012) Organelle positioning in muscles requires cooperation between two KASH proteins and microtubules. J Cell Biol 198:833-46
Anand, Preetha; Cermelli, Silvia; Li, Zhihuan et al. (2012) A novel role for lipid droplets in the organismal antibacterial response. Elife 1:e00003
Li, Zhihuan; Thiel, Katharina; Thul, Peter J et al. (2012) Lipid droplets control the maternal histone supply of Drosophila embryos. Curr Biol 22:2104-13
Yu, Yanxun V; Li, Zhihuan; Rizzo, Nicholas P et al. (2011) Targeting the motor regulator Klar to lipid droplets. BMC Cell Biol 12:9
Hain, Daniel; Bettencourt, Brian R; Okamura, Katsutomo et al. (2010) Natural variation of the amino-terminal glutamine-rich domain in Drosophila argonaute2 is not associated with developmental defects. PLoS One 5:e15264

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