The goal of this research is to provide information on the growth and guidance of axons within the central nervous system, using the formation of crossed and uncrossed projections of the retina in the mouse visual system as a model. Recent work in our laboratory has demonstrated the pattern of retinal axon growth through the optic chiasm, the site where retinal axons sort before projecting to targets on the same and opposite sides of the brain. These studies, based on dye-labeling in fixed brain and real time studies of dye-labeled axons in living brain, indicate that whereas contralateral-projecting axons traverse the chiasm midline, fibers with an ipsilateral destination approach the midline, but turn back sharply toward the ipsilateral optic tract. An important feature of fiber divergence within the chiasm appears to be inhibition of uncrossed fiber extension and permissive advance of crossed fibers at the chiasm midline. We have localized a palisade of radial glia restricted to the midline zone, a candidate for such a dual cue. Moreover, studies based on unilateral eye removal suggest that interactions with fibers from the opposite eye are required to fully effect axon divergence of uncrossed fibers. The proposed research will provide information on the mechanism of axon guidance in the optic chiasm. First, the behavior and interactions of retinal axon growth cones with cellular constituents of the midline zone will be defined, using dye labeling in fixed and living preparations, combined with immunocytochemistry and electron microscopy. In vitro assay systems will be developed by which to test the role of cells in the chiasm midline in inhibition or extension across the midline, and whether contact and/or tropic mechanisms are involved. Second, the role of fiber-fiber interactions will be investigated as an auxilliary mechanism in the divergence. Third, this system and analysis will be used to define in a wider sense, how growth cone morphology reflects growth cone behavior and cell-cell interactions. This work should elucidate the signalling mechanisms used for axon navigation in this CNS pathway, a model for the patterning of bilateral projections, and provide a dynamic analysis of growth cone kinetics and interactions.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Visual Sciences B Study Section (VISB)
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Columbia University (N.Y.)
Schools of Medicine
New York
United States
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Marcus, R C; Matthews, G A; Gale, N W et al. (2000) Axon guidance in the mouse optic chiasm: retinal neurite inhibition by ephrin ""A""-expressing hypothalamic cells in vitro. Dev Biol 221:132-47
Marcus, R C; Shimamura, K; Sretavan, D et al. (1999) Domains of regulatory gene expression and the developing optic chiasm: correspondence with retinal axon paths and candidate signaling cells. J Comp Neurol 403:346-58
Mason, C A; Wang, L C (1997) Growth cone form is behavior-specific and, consequently, position-specific along the retinal axon pathway. J Neurosci 17:1086-100
Wang, L C; Rachel, R A; Marcus, R C et al. (1996) Chemosuppression of retinal axon growth by the mouse optic chiasm. Neuron 17:849-62
Marcus, R C; Wang, L C; Mason, C A (1996) Retinal axon divergence in the optic chiasm: midline cells are unaffected by the albino mutation. Development 122:859-68
Marcus, R C; Blazeski, R; Godement, P et al. (1995) Retinal axon divergence in the optic chiasm: uncrossed axons diverge from crossed axons within a midline glial specialization. J Neurosci 15:3716-29
Marcus, R C; Mason, C A (1995) The first retinal axon growth in the mouse optic chiasm: axon patterning and the cellular environment. J Neurosci 15:6389-402
Wang, L C; Dani, J; Godement, P et al. (1995) Crossed and uncrossed retinal axons respond differently to cells of the optic chiasm midline in vitro. Neuron 15:1349-64
Wang, L C; Baird, D H; Hatten, M E et al. (1994) Astroglial differentiation is required for support of neurite outgrowth. J Neurosci 14:3195-207
Baird, D H; Baptista, C A; Wang, L C et al. (1992) Specificity of a target cell-derived stop signal for afferent axonal growth. J Neurobiol 23:579-91

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