Abstract
BackgroundLongitudinal axons grow parallel to the embryonic midline to connect distant regions of the central nervous system. Previous studies suggested that repulsive midline signals guide pioneer longitudinal axons by blocking their entry into the floor plate; however, the role of midline attractants, and whether attractant signals may cooperate with repulsive signals, remains unclear. In this study we investigated the navigation of a set of pioneer longitudinal axons, the medial longitudinal fasciculus, in mouse embryos mutant for the Netrin/Deleted in Colorectal Cancer (DCC) attractants, and for Slit repellents, as well as the responses of explanted longitudinal axons in vitro.ResultsIn mutants for Netrin1 chemoattractant or DCC receptor signaling, longitudinal axons shifted away from the ventral midline, suggesting that Netrin1/DCC signals act attractively to pull axons ventrally. Analysis of mutants in the three Slit genes, including Slit1/2/3 triple mutants, suggest that concurrent repulsive Slit/Robo signals push pioneer axons away from the ventral midline. Combinations of mutations between the Netrin and Slit guidance systems provided genetic evidence that the attractive and repulsive signals balance against each other. This balance is demonstrated in vitro using explant culture, finding that the cues can act directly on longitudinal axons. The explants also reveal an unexpected synergy of Netrin1 and Slit2 that promotes outgrowth.ConclusionsThese results support a mechanism in which longitudinal trajectories are positioned by a push-pull balance between opposing Netrin and Slit signals. Our evidence suggests that longitudinal axons respond directly and simultaneously to both attractants and repellents, and that the combined signals constrain axons to grow longitudinally.
Highlights
Longitudinal axons grow parallel to the embryonic midline to connect distant regions of the central nervous system
Netrin1 is expressed along the path of the medial longitudinal fasciculus The MLF is one of the first tracts to form in the vertebrate brain and becomes a major conduit for fiber populations involved in motor coordination [39]
The hindbrain floor plate expression of Netrin1 overlaps with expression of all three Slit genes [21], which together indicates that the MLF axons are exposed to high levels of both Netrin1 and Slits as they project longitudinally adjacent to the hindbrain floor plate
Summary
Longitudinal axons grow parallel to the embryonic midline to connect distant regions of the central nervous system. Longitudinal trajectories require a source of cues sustained along their ipsilateral trajectories Because they project parallel to the longitudinal axis of the brain stem, a potential source of cues for the pioneer longitudinal tracts is the floor plate tissue along the ventral midline, which produces long range and local cues [7]. The major secreted cues for vertebrate commissural axons are Netrin via its main attractive receptor Deleted in Colorectal Cancer (DCC) [10,11,12,13], and the three Slits via their family of repulsive Robo receptors, primarily Robo and 2 [14,15,16]. Longitudinal axons grow parallel to the floor plate but through the same environment as commissural axons, and could be guided by the same attractive and repulsive signals. Robo and 2 appear to guide pioneer longitudinal axons in a redundant, rather than code-like, manner [18,27]
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