Abstract
Commissural axons must cross the midline to establish reciprocal connections between the two sides of the body. This process is highly conserved between invertebrates and vertebrates and depends on guidance cues and their receptors to instruct axon trajectories. The DCC family receptor Frazzled (Fra) signals chemoattraction and promotes midline crossing in response to its ligand Netrin. However, in Netrin or fra mutants, the loss of crossing is incomplete, suggesting the existence of additional pathways. Here, we identify Brain Tumor (Brat), a tripartite motif protein, as a new regulator of midline crossing in the Drosophila CNS. Genetic analysis indicates that Brat acts independently of the Netrin/Fra pathway. In addition, we show that through its B-Box domains, Brat acts cell autonomously to regulate the expression and localization of Adenomatous polyposis coli-2 (Apc2), a key component of the Wnt canonical signaling pathway, to promote axon growth across the midline. Genetic evidence indicates that the role of Brat and Apc2 to promote axon growth across the midline is independent of Wnt and Beta-catenin-mediated transcriptional regulation. Instead, we propose that Brat promotes midline crossing through directing the localization or stability of Apc2 at the plus ends of microtubules in navigating commissural axons. These findings define a new mechanism in the coordination of axon growth and guidance at the midline.
Highlights
Organisms with bilateral symmetry coordinate the left and right sides of their body by establishing reciprocal connections in the central nervous system
Axons that cross the midline to form these connections are called commissural axons and the molecules and mechanisms that control midline axon crossing are remarkably conserved across animal evolution
In this study we have used a genetic screen in the fruit fly in an attempt to uncover additional players in this key developmental process, and have identified a novel role for the Brain Tumor (Brat) protein in promoting commissural axon growth across the midline
Summary
Organisms with bilateral symmetry coordinate the left and right sides of their body by establishing reciprocal connections in the central nervous system. Despite the clear importance of Netrin signaling in promoting axon growth across the midline, many axons still cross the midline in netrinAB double mutants or fra mutants in Drosophila. This indicates that additional pathways must promote midline crossing [11,12]. Many other mechanisms have been described that promote axon growth across the midline by preventing premature responses to repulsive molecules secreted from the midline, such as Slits and Semaphorins [16,17,18,19,20] Despite this progress, it is clear from genetic analysis that additional pathways are likely to be required to ensure the precise regulation of midline circuit formation
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