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• W146484313 abstract "In the developing vertebrate brain neurons differentiate in largely invariant locations and axons project with remarkable precision to innervate specific targets. While the general principles of axon growth and guidance are understood in vitro, much less is known about these processes in vivo. Recent studies suggest that a complex interplay of chemorepulsive and chemoattractive cues are necessary for establishing the early scaffold of axon tracts in the vertebrate brain. This thesis reports the identification, characterisation and functional analysis of three putative axon guidance molecules: Xenopus Roundabout-1, zebrafish Roundabout-3 and brother of CDO (Cell adhesion molecule-related/Down regulated by Oncogenesis). All are members of the immunoglobulin (Ig) superfamily members and all are involved in the growth and guidance of axons in the embryonic vertebrate brain. The receptor Roundabout-1 (Robol) and its ligand Slit are known to infiuence axon guidance and central nervous system (CNS) patterning in both vertebrate and nonvertebrate systems. Although Robo-Slit interactions mediate axon guidance in the Drosophila CNS, their role in establishing the early axon scaffold in the embryonic vertebrate brain remains unclear. This thesis reports the identification and expression of a Xenopus Robol1 orthologue that is highly homologous to mammalian Robo1. The role of Robo1 in the development of a subset of neurons and axon tracts in the Xenopus forebrain was investigated using overexpression studies, immunohistochemical and in situ hybridisation techniques. Robo1 is expressed in forebrain nuclei and in neuroepithelial cells underlying the main axon tracts. Misexpression of Robo1 led to aberrant development of axon tracts as well as the ectopic differentiation of forebrain neurons. These results implicate Robol in both neuronal differentiation and axon guidance in embryonic vertebrate forebrain. In zebrafish, two forms of the putative axon guidance molecule roundabout-3 (Robo3) have been reported and are described in this thesis as Robo3a and 3b. The role of Robo3b in axon guidance in the zebrafish forebrain was analysed using immunohistochemical techniques, misexpression and antisense morpholino oligonucleotides. Robo3b is expressed in the main nuclei of the fore-, mid- and hindbrain as well as in cells outside of the nervous system. Analysis of Robo3b gain-of-function and loss-of-function mutant zebrafish embryos revealed defects in both dorsoventral and rostro-caudal projecting axon tracts. These results indicate that Robo3b is functionally active and plays select roles in axon navigation during formation of the early axon scaffold in the embryonic vertebrate brain. Brother of CDO has previously been shown to positively regulate myogenic differentiation in vitro and is expressed in a restricted pattern in the dorsal neural tube in the mouse. This thesis reports the isolation of a zebrafish orthologue of BOC (zboc) and describes its expression pattern, zboc is expressed in a variety of tissues firom early in development and its distribution is consistent with multiple functional roles. In the brain zboc is prominent in the ventricular margin of the dorsal neural tube. The role of zboc was first assessed in gain-of-function mutants following injection of zboc mRNA into one-cell embryos. These animals suffered severe defects in the patterning of the rostrocaudal axis typical of dorsalised embryos. Loss-of-function mutants were also produced using a zboc antisense morpholino oligonucleotide. Analysis of embryos injected at the one-cell stage revealed consistent defects in the dorsoventrally projecting axon tracts in the rostral brain. This thesis presents the first functional evidence for the role of Xenopus Roundabout-1, zebrafish Roundabout-3 and brother of CDO in the development of a stereotypical axon scaffold in the vertebrate brain. It provides a foundation for fiiture research into the complex interactions that control the growth and guidance of axons in vivo.n" @default.
• W146484313 created "2016-06-24" @default.
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• W146484313 date "2003-01-01" @default.
• W146484313 modified "2023-09-23" @default.
• W146484313 title "Mechanisms of axon growth and guidance in the vertebrate nervous system" @default.
• W146484313 hasPublicationYear "2003" @default.
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