In the nervous systems of bilaterians, specialized cells located at the midline of the neuroectoderm play an essential role in organizing the development of the CNS (Tessier-Lavigne and Goodman, 1996; Dickson, 2002). In insects and vertebrates, cells of the CNS midline are known to represent inductive centers for the regional patterning of the neuroecto-derm. Moreover, the CNS midline represents an important intermediate target where growing axons either cross and project contralaterally or remain on the same side of the body. The midline cells express at their surface membrane-bound guidance molecules and secrete diffusible factors that act as attractive or repulsive guidance cues and guide growing axons from a distance; under the influence of these molecules, some axons avoid the midline, whereas others grow toward it and cross it once.
The developmental control genes that specify these midline cell populations appear to differ between insects and vertebrates. In Drosophila, formation of midline cells requires the specific expression of the single-minded gene (Nambu et al., 1990), whereas in vertebrates, the formation of midline cells requires the specific expression of HNF3beta (Ang and Rossant, 1994; Weinstein et al., 1994). Also, the morphogens that mediate the inductive interactions of the midline cells differ in vertebrates versus insects. In vertebrates, Sonic hedgehog signaling from the floor plate exerts its patterning function on the adjacent dorsal neuroec-toderm (Ho and Scott, 2002), whereas in Drosophila, EGF signaling exerts patterning on the adjacent ventral neuroectoderm (Skeath, 1999).
In contrast, many aspects of midline cell-mediated axon guidance are controlled by functionally and evolutionarily conserved ligand-receptor systems that include the Netrin, DCC, Slit, and Robo gene families (Araujo and Tear, 2002; Kaprielian et al., 2001). Homologous Netrin genes encode soluble attractor molecules that are detected in the floor plate and ventral neural tube of vertebrates as well as in the midline glial cells of Drosophila and that serve to guide commissural axons toward the midline. In both cases, the Netrins are expressed at a time when first commissural growth cones, which express the homologous frazzled/DCC genes that encode transmembrane receptors, are extending toward the midline. Netrin mutant embryos exhibit defects in commissural axon projections in mice and flies, indicating similar functional roles of these attractants. Moreover, in Drosophila as well as in vertebrates, axonal projections away from the midline depend on the presence at the midline of a repellent molecule, which binds and interacts with axonal receptors. In Drosophila, the midline repellent that expels commis-sural axons and prevents them from recrossing is the ligand Slit, which mediates its repulsive effects via receptors of the Roundabout (Robo) family that are dynamically expressed on commissural axons. In vertebrates, three Slit homologues (Slit1, Slit2, and Slit3) and three Robo homologues (Robo1, Robo2, and Rig-1) have been identified, with expression patterns reminiscent of their Drosophila counterparts. The vertebrate Slit genes are expressed in the floor plate at the ventral midline of the spinal cord, and their corresponding Robo1 and 2 receptors are expressed by commissural axons. Studies indicate that vertebrate commissural axons become insensitive to floor plate attraction and sensitive to Slit-mediated repulsion after crossing the midline; this modulation of repulsion at the midline is reminiscent of the situation in the Drosophila CNS.
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