Biological Sciences

Dennis D.M. O'Leary Professor of Biology, The Salk Institute e-mail: doleary@salk.edu

    We study vertebrate neural development with a focus on the mammalian cortex and the visual system of mammals and chicks.  We use in vivo and in vitro experimental approaches employing anatomical, cellular and molecular techniques to study phenomena such as (1) the differentiation of functionally specialized areas of the mammalian cortex, (2) pathway selection and target recognition by developing axons, and (3) the establishment of ordered connections between the retina and its central
targets. Our goals are to characterize these phenomena, to define the cellular and molecular mechanisms that control them, and to relate their significance to the establishment of the functional organization of the relevant neural systems. 

DEVELOPMENT OF THE NEOCORTEX
     This project is directed towards unraveling the mechanisms which direct the correct anatomical and functional organization of the mammalian cortex. The mammalian neocortex processes visual, auditory, and somatic sensation and gives rise to perception, volitional motor responses, and learning and memory. These diverse operations are performed by functionally specialized areas of the neocortex each characterized by unique connectivity and architecture. Presently, we are (1) examining
modes of cell migration in the cortex, (2) studying the molecular control of the establishment of area-specific thalamocortical connections, and (3) determining the expression and function of certain regulatory genes which may control the development of area-specific properties. 

AXON GUIDANCE AND TARGET SELECTION
     As a model system for investigating the means by which neurons recognize and innervate their targets, we have been studying the development of the axonal projections of cortical layer 5 neurons to their targets in the midbrain, hindbrain and spinal cord.  The conscious control of bodily movements is mediated by this projection. Presently, we are (1) studying the dynamics of target recognition by layer 5 axons using time-lapse video microscopy, (2) investigating the role of neurotrophins in establishing the cellular architecture and connections of layer 5 neurons, and (3) attempting to identify other molecules, including a novel chemoattractant involved in the development of these connections. 

MECHANISMS GOVERNING THE DEVELOPMENT OF VISUAL CONNECTIONS 
     The goal of this project is to characterize the mechanisms which direct the correct anatomical and functional organization of the vertebrate visual system, and in particular the topographic ordering of retinal connections within central visual centers. We are presently studying (1) the behavior of retinal axons leading to the formation of topographically ordered synaptic connections, (2) the distribution of the Eph subfamily of receptor tyrosine kinases and ligands and their role in guiding retinal axons, and (3) the genetic regulation of retinotopic maps. 

      Frisén, J., Yates, P.A., McLaughlin, T., Friedman, G.C., O'Leary, D.D.M. and Barbacid, M. (1998). Ephrin-A5 (AL-1/RAGS) is essential for proper retinal axon guidance and topographic mapping in the mammalian visual system. Neuron 20:235-243. 

      Tuttle, R. and O'Leary, D.D.M. (1998). Neurotrophins rapidly modulate growth cone response to the axon guidance molecule, collapsin-1. Molecular and Cellular Neurobiology 11:1-8. 

      Richards, L.R., Koester, S.E., Tuttle, R. and O'Leary, D.D.M. (1997). Directed growth of early cortical axons is influenced by a chemoattractant released from an intermediate target. Journal of Neuroscience 17:2445-2458. 

      Braisted, J.E., McLaughlin, T., Wang, H.U., Friedman, G.C., Anderson, D.J. and O'Leary, D.D.M. (1997). Graded and lamina-specific distributions of ligands of EphB receptor tyrosine kinases in the developing retinotectal system. Developmental
Biology 191:14-28.