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.
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