The axonal transport system is known to play a key role in maintaining the structural and functional integrity of axons. A defective axonal transport system may contribute to the etiology of certain nerve degenerative diseases and peripheral neuropathies associated with exposure to neurotoxic chemicals. Although much information on the transport of axonal constituents (especially proteins) has been obtained using radioactive tracer techniques, the structural and molecular bases axonal transport remain elusive. Recently, we reported the discovery of a microtubule (MT)-associated """"""""coupler"""""""" in axons. This structure links MTs to other cytoskeletal components as well as to various types of membrane-bound organelles (MBOs) and redistributes so as to remain associated with MTs in axons treated with B,B'-iminodipropionitrile (IDPN). These findings along with those of previous studies suggest that couplers are involved in the generation of motive forces for fast axonal transport. The main objectives of the proposed study are to further our understanding of (1) the structure, composition and function of couplers in axons and (2) the relationship of couplers to cytoskeletal elements during nerve growth and axonal transport. The following major approaches are planned: (1) More rapid and improved fixation methods will be used to reveal structures that participate in axonal transport. (2) Segregation of MTs and neurofilaments induced with B,B""""""""-iminodipropionitrile will be used as a model system to study the individual roles of MTs, NFs and couplers in nerve growth and axonal transport. (3) Correlated time-lapse cinemicrography and electron microscopy will be used to relate directly variations in the nerve growth rate with changes in the number and distribution of couplers and the organizational state of the axonal cytoskeleton. (4) Immunocytochemical techniques will be used to examine the composition of couplers. The studies will help elucidate the structural and molecular bases of nerve growth and axonal transport which, in turn, will shed new light on the underlying causes of axonopathies associated with certain neurotoxic and nerve degenerative diseases which may be due, at least in part, to a defective axonal transport system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Unknown (R23)
Project #
5R23NS021730-03
Application #
3449791
Study Section
Neurology B Subcommittee 1 (NEUB)
Project Start
1986-04-01
Project End
1989-03-31
Budget Start
1988-04-01
Budget End
1989-03-31
Support Year
3
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Type
Schools of Osteopathy
DUNS #
City
Stratford
State
NJ
Country
United States
Zip Code
08084
Nagele, R G; Bush, K T; Hunter, E T et al. (1989) Biomechanical basis of diazepam-induced neural tube defects in early chick embryos: a morphometric study. Teratology 40:29-36
Lee, H; Bush, K T; Nagele, R G (1988) Time-lapse photographic study of neural tube closure defects caused by xylocaine in the chick. Teratology 37:263-9
Nagele, R G; Bush, K T; Lee, H Y (1988) A morphometric study of cytoskeletal reorganization in rat sciatic nerve axons following beta,beta'-iminodipropionitrile (IDPN) treatment. Neurosci Lett 92:241-6
Nagele, R G; Kosciuk, M C; Hunter, E T et al. (1988) Immunoelectron microscopic localization of actin in neurites of cultured embryonic chick dorsal root ganglia: actin is a component of granular, microtubule-associated crossbridges. Brain Res 474:279-86
Lee, H; Nagele, R G (1988) Intrinsic forces alone are sufficient to cause closure of the neural tube in the chick. Experientia 44:60-1
Nagele, R G; Lee, H Y (1987) Studies on the mechanisms of neurulation in the chick: morphometric analysis of the relationship between regional variations in cell shape and sites of motive force generation. J Exp Zool 241:197-205
Nagele, R G; Lee, H (1987) A new method for the preparation of 'double-fixed', quick-frozen, freeze-substituted cells for whole-cell transmission electron microscopy. J Microsc 148:89-95
Nagele, R G; Hunter, E; Bush, K et al. (1987) Studies on the mechanisms of neurulation in the chick: morphometric analysis of force distribution within the neuroepithelium during neural tube formation. J Exp Zool 244:425-36