Neurons extend axons over long distances to reach their target tissues during normal development and also during regeneration following injury. A growing body of evidence indicates that the growth and maintenance of the axon is dependent upon its cytoskeletal structure, and in particular of its microtubules. Microtubules are filamentous proteins that have important functions in generating and maintaining cellular architecture, regulating motile events in the cell, and in organizing the cytoplasm to carry out essential metabolic processes. Within the axon, microtubules are uniformly oriented with their """"""""plus"""""""" ends distal to the cell body, and this organization is essential for directing organelle traffic in the axon. Unfortunately, the mechanisms by which the microtubule array of the axon is elaborated and organized are poorly understood, and a matter of some controversy. In particular, there has been disagreement with regard to the sites where axonal microtubules originate, and the relative contributions of microtubule assembly and transport to the growth of the axon. This application represents the continuation of efforts to address these questions. Recent indirect evidence suggests that axonal microtubules originate at the centrosome, and are then released for translocation into and down the axon. If this is correct, then there is a shift during transit from a large number of short microtubules to a smaller number of very long microtubules within the axon. With regard to the organization of these microtubules, an attractive possibility is that the translocation of microtubules through the cytoplasm occurs exclusively with plus-ends leading, thereby establishing the uniform polarity orientation of microtubules within the axon. In this application, experiments are proposed that will evaluate the role of the centrosome in generating axonal microtubules, and determine the relative contributions of microtubule transport and assembly to axon growth. Other experiments will specifically address whether the transport properties of axonal microtubules can account for their plus-end-distal polarity orientation. Finally, efforts will be directed toward measuring in very fine detail the lengths of individual microtubules throughout the axon. Collectively, the information derived from these studies will resolve important issues about axonal microtubules, and thereby provide new insights into the mechanisms by which the axonal microtubule array is elaborated and organized. Information of this kind is essential for understanding the cell biology of the neuron, and for elucidating the causes and potential cures for neuropathologies that involve axonal degeneration and/or retardation of axon growth.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS028785-09
Application #
2519937
Study Section
Special Emphasis Panel (ZRG1-NEUB-1 (03))
Program Officer
Cheung, Mary Ellen
Project Start
1990-09-01
Project End
1998-08-31
Budget Start
1997-09-01
Budget End
1998-08-31
Support Year
9
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Miscellaneous
Type
Schools of Earth Sciences/Natur
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Rao, Anand N; Baas, Peter W (2018) Polarity Sorting of Microtubules in the Axon. Trends Neurosci 41:77-88
Solowska, Joanna M; Rao, Anand N; Baas, Peter W (2017) Truncating mutations of SPAST associated with hereditary spastic paraplegia indicate greater accumulation and toxicity of the M1 isoform of spastin. Mol Biol Cell 28:1728-1737
Craig, Erin M; Yeung, Howard T; Rao, Anand N et al. (2017) Polarity sorting of axonal microtubules: a computational study. Mol Biol Cell 28:3271-3285
Rao, Anand N; Patil, Ankita; Black, Mark M et al. (2017) Cytoplasmic Dynein Transports Axonal Microtubules in a Polarity-Sorting Manner. Cell Rep 19:2210-2219
Rao, Anand N; Patil, Ankita; Brodnik, Zachary D et al. (2017) Pharmacologically increasing microtubule acetylation corrects stress-exacerbated effects of organophosphates on neurons. Traffic 18:433-441
Leo, Lanfranco; Weissmann, Carina; Burns, Matthew et al. (2017) Mutant spastin proteins promote deficits in axonal transport through an isoform-specific mechanism involving casein kinase 2 activation. Hum Mol Genet 26:2321-2334
Matamoros, Andrew J; Baas, Peter W (2016) Microtubules in health and degenerative disease of the nervous system. Brain Res Bull 126:217-225
Feng, Jie; Hu, Zunlu; Chen, Haijiao et al. (2016) Depletion of kinesin-12, a myosin-IIB-interacting protein, promotes migration of cortical astrocytes. J Cell Sci 129:2438-47
Kahn, Olga I; Baas, Peter W (2016) Microtubules and Growth Cones: Motors Drive the Turn. Trends Neurosci 39:433-440
Rao, Anand N; Falnikar, Aditi; O'Toole, Eileen T et al. (2016) Sliding of centrosome-unattached microtubules defines key features of neuronal phenotype. J Cell Biol 213:329-41

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