Philip F. Copenhaver

Ph.D., University of Washington, 1985

Associate Professor, Cell and Developmental Biology

During the formation of the nervous system, most neurons must migrate over extensive distances to reach their correct locations. What are the molecular mechanisms that control this process? We use an insect embryonic preparation to investigate the role of specific guidance cues and intracellular signaling molecules during the migration of identified neurons in the intact nervous system. Unlike vertebrate preparations, the migratory neurons in this system are directly accessible to experimental manipulations within the developing embryo, yet behave similarly to neurons in more complex systems. Antibodies that specifically label the neurons and intracellular injections of fluorescent dyes are used to monitor neuronal migratory behavior in culture preparations. Genes encoding candidate guidance cues (including fasciclins, semaphorins, and other receptors) are cloned to generate probes (blocking antibodies, antisense oligonucleotides, plasmids to induce ectopic expression), which are used to manipulate the activity of these receptors in vivo. Constitutively active and dominant negative forms of intracellular signaling molecules (including G proteins and tyrosine kinases) can be injected to test their role in transducing the response of a neuron to specific guidance cues. Calcium-sensitive dyes and fluorescent cytoskeletal monomers (actin and tubulin) are also used to determine the effects of experimental manipulations on key aspects of cellular motility. Questions currently being investigated include: What are the guidance cues and signaling mechanisms required to initiate migration? What is the primary stop signal for migration and can neurons compensate for its loss? And how do neurons integrate positive and negative stimuli into coherent changes in behavior? The unique features of this experimental preparation also allow us to test the role of molecules that have been implicated in diseases of the nervous system, including the amyloid precursor protein (associated with Alzheimer's Disease) and the effects of novel antimetastatic agents on neuronal migration.

Wright, J., and Copenhaver, P.F. (2000). Different isoforms of fasciclin II play distinct roles in the guidance of neuronal migration during insect embryogenesis. Dev. Biol. 225, 59-78.

Horgan, A.M., and Copenhaver, P.F. (1998) G Protein-mediated inhibition of neuronal migration requires calcium influx. J. Neurosci. 18:4189-4200.

Wright, J.W., Schwinof, K.M., Snyder, M.A., and Copenhaver, P.F. (1998). A delayed role for nitric oxide-sensitive guanylate cyclases in a migratory population of embryonic neurons. Dev. Biol. 204, 15-33.

To contact Dr. Copenhaver directly: copenhav@ohsu.edu