sidestep Encodes a Target-Derived Attractant Essential for Motor Axon Guidance in Drosophila

Abstract

At specific choice points in the periphery, subsets of motor axons defasciculate from other axons in the motor nerves and steer into their muscle target regions. Using a large-scale genetic screen in Drosophila, we identified the sidestep (side) gene as essential for motor axons to leave the motor nerves and enter their muscle targets. side encodes a target-derived transmembrane protein (Side) that is a novel member of the immunoglobulin superfamily (IgSF). Side is expressed on embryonic muscles during the period when motor axons leave their nerves and extend onto these muscles. In side mutant embryos, motor axons fail to extend onto muscles and instead continue to extend along their motor nerves. Ectopic expression of Side results in extensive and prolonged motor axon contact with inappropriate tissues expressing Side.

The metalloprotease Tolloid-related and its TGF-β-like substrate Dawdle regulateDrosophilamotoneuron axon guidance

“…In addition, because motor axons still adhere to each other in the periphery of Fas2 mutants, redundant adhesion molecules must exist to maintain peripheral fasciculation. Genetic screens in Drosophila have uncovered several mutations including the beaten path (beat), sidestep (side) and receptor-linked protein tyrosine phosphatases (RPTPs), whose loss-of-function phenotypes are similar to Fas2 gain-of-function phenotypes, suggesting that the products of these loci help drive de-fasciculation (de Jong et al, 2005;Desai et al, 1996;Desai et al, 1997;Krueger et al, 1996;Pipes et al, 2001;Schindelholz et al, 2001;Sink et al, 2001).…”

Drosophila neurotrophins reveal a common mechanism for nervous system formation

“…Abundant evidence indicates that motor neurons live and function well in the absence of the muscle target in Drosophila [96]. For instance, upon genetic elimination or surgical ablation of the muscle [97][98][99] and in the absence of muscle-derived signals [100], motor neurons grow towards the muscle but fail to target or target to ectopic sites. In normal embryos and larvae, the projection patterns of motor neurons is very stereotypic [96,101,102].…”

No Sidesteps on a beaten track

“…Of the known axon guidance regulators, Sidestep (Side) represents a promising candidate molecule that could be a determinant of such a pathway, as it has been shown to function as a target-derived attractant for motor axons. 10 Side is expressed in a complex spatiotemporal pattern during embryonic development, but its expression in sensory neurons and muscles coincides with the arrival of motor axons at these intermediate and final targets, respectively. 10 Since Side is a transmembrane protein, it most likely functions as a contact attractant, suggesting that its expression pattern provides pathway information.…”

“…10 Side is expressed in a complex spatiotemporal pattern during embryonic development, but its expression in sensory neurons and muscles coincides with the arrival of motor axons at these intermediate and final targets, respectively. 10 Since Side is a transmembrane protein, it most likely functions as a contact attractant, suggesting that its expression pattern provides pathway information. Simultaneous visualization of both motor axons and Side-expressing cells reveals an intriguing spatiotemporal relationship between these cell types.…”

“…It is then upregulated in muscle fibers. 10 Side-positive muscle fibers likely attract the growth cones and cause them to leave the sensory tracks. In this respect, it is interesting to note that motor axons have been found to end up in clusters of sensory neurons when deprived of their target muscles.…”