The long-term goal of our laboratory is to understand how neurons decide to change from one state to another, and how this decision is expressed as an alteration of their molecular configurations. Toward this end we propose to investigate four problems concerned with the role of axonally transported proteins in the maintenance and changes in neuronal state. First, we will study the state in which a neuron extends its axon. Certain proteins, designated growth associated proteins, or GAPS, are axonally transported into growing axons at much higher levels than into axons of the stationary state; this suggests that they perform functions required only in axon growth. We propose to determine whether one of these polypeptides, GAP-43, is a component of the neuronal growth cone, and to determine how its function is modified post-translationally by phosphorylation by a calcium and calmodulin-dependent protein kinase. We will also investigate how the axonal transport of GAP-43 is regulated to insure its transport only during periods of axon growth. Second, we will investigate the change of state that occurs during neuronal development when the neurofilamentous cytoskeleton is first crosslinked by the protein H. We will attempt to determine the function of this crosslinking protein by observing physiological changes that are a consequence of a genetic alteration in H. In addition, we will determine how H is synthesized and how it is delivered specifically to the axon. The third problem we will investigate is how a protein (fodrin) that resembles erythrocyte-spectrin functions to maintain the steady-state axon. We will study how fodrin interacts with other proteins in the nervous system, and how it functions in the process of capping of surface molecules in lymphocytes. Fourth, we will investigate how certain rapidly transported proteins are supplied to the axon.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY002682-13
Application #
3257020
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1978-06-01
Project End
1990-05-31
Budget Start
1987-06-01
Budget End
1988-05-31
Support Year
13
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Washington University
Department
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Spencer, S A; Schuh, S M; Liu, W S et al. (1992) GAP-43, a protein associated with axon growth, is phosphorylated at three sites in cultured neurons and rat brain. J Biol Chem 267:9059-64
Spencer, S; Willard, M B (1992) Does GAP-43 support axon growth by increasing the axonal transport velocity of calmodulin? Exp Neurol 115:167-72
Xu, Z S; Liu, W S; Willard, M B (1992) Identification of six phosphorylation sites in the COOH-terminal tail region of the rat neurofilament protein M. J Biol Chem 267:4467-71
Soppet, D R; Beasley, L L; Willard, M B (1992) Evidence for unequal crossing over in the evolution of the neurofilament polypeptide H. J Biol Chem 267:17354-61
Loewy, A; Liu, W S; Baitinger, C et al. (1991) The major 35S-methionine-labeled rapidly transported protein (superprotein) is identical to SNAP-25, a protein of synaptic terminals. J Neurosci 11:3412-21
Schuh, S M; Spencer, S; Willard, M B (1991) Production of the neuronal growth-associated protein GAP-43 in a bacterial expression system. Brain Res 565:85-93
Soppet, D R; Beasley, L L; Willard, M B (1991) Sequence of the rabbit neurofilament protein L. J Neurosci Res 30:42-6
Baitinger, C; Willard, M (1987) Axonal transport of synapsin I-like proteins in rabbit retinal ganglion cells. J Neurosci 7:3723-35
Willard, M; Baitinger, C; Cheney, R (1987) Translocations of fodrin and its binding proteins. Brain Res Bull 18:817-24
Meiri, K F; Pfenninger, K H; Willard, M B (1986) Growth-associated protein, GAP-43, a polypeptide that is induced when neurons extend axons, is a component of growth cones and corresponds to pp46, a major polypeptide of a subcellular fraction enriched in growth cones. Proc Natl Acad Sci U S A 83:3537-41

Showing the most recent 10 out of 11 publications