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Crossing the embryonic midline: molecular mechanisms regulating axon responsiveness at an intermediate target

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In bilaterally symmetric animals, the precise assembly of neural circuitry at the midline is essential for coordination of the left and right sides of the body. Commissural axons must first be directed across the midline and then be prevented from re‐crossing in order to ensure proper midline connectivity. Here, we review the attractants and repellents that direct axonal navigation at the ventral midline and the receptors on commissural neurons through which they signal. In addition, we discuss the mechanisms that commissural axons use to switch their responsiveness to midline‐derived cues, so that they are initially responsive to midline attractants and subsequently responsive to midline repellents. WIREs Dev Biol 2015, 4:377–389. doi: 10.1002/wdev.185 This article is categorized under: Nervous System Development > Flies Nervous System Development > Vertebrates: General Principles
Comm regulates Slit responsiveness by inhibiting trafficking of Robo to the growth cone. In Drosophila, as commissural neurons grow toward the midline, they express the endosomal protein Comm, which targets newly synthesized Robo for lysosomal degradation. Fra regulates comm transcription independent of its canonical ligands, Netrins. After crossing, Comm expression is extinguished and Robo is trafficked to the growth cone, where it signals repulsion in response to Slit.
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GDNF modulates Sema3B responsiveness by regulating PlexA1 proteolysis. As spinal commissural axons are growing toward the midline, calpain cleaves the Sema3B receptor PlexA1 to reduce sensitivity to Sema3B. When these neurons reach the midline, GDNF signals through NCAM and its co‐receptor GFRα1 to reduce calpain activity. Sema3B then signals repulsion through Nrp2 and PlexA1.
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Robo3 regulates Slit responsiveness of commissural axons. In pre‐crossing spinal commissural neurons, Robo3.1 inhibits Slit repulsion through Robo1 and Robo2. After crossing, Robo3.1 is no longer expressed and Robo3.2 collaborates with Robo1 and Robo2 to signal midline repulsion.
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Commissural axons switch the polarity of their response to Shh. Pre‐crossing spinal commissural neurons signal attraction to midline‐derived Shh through the receptor Boc. These neurons turn anteriorly after they have crossed the midline, in response to a posterior high to anterior low gradient of Shh, but the relevant Shh receptor is not known. 14‐3‐3 is specifically expressed in post‐crossing commissural neurons and is required for Shh‐dependent repulsion, but not attraction. Both attractive and repulsive Shh signaling depend on Smo, but it is not clear whether the Shh co‐receptor Patched, which relieves repression of Smo to permit Shh signaling in other contexts, is required for Shh‐dependent attraction or repulsion.
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Commissural interneurons in the embryonic spinal cord of mouse and ventral nerve cord of Drosophila. (a) Transverse section of the mouse spinal cord at embryonic day 11.5. Pre‐crossing spinal commissural neurons navigate ventromedially and express the cell adhesion molecule Tag1. (b) Transverse section of the mouse spinal cord at embryonic day 11.5. Post‐crossing commissural neurons express the cell adhesion marker L1. (c) Open‐book preparation of the mouse spinal cord at embryonic day 11.5. Spinal commissural neurons are labeled by DiI injection into the dorsal spinal cord. The majority of post‐crossing commissural axons turn anteriorly. The bracket indicates the position of the floor plate. (d) Three segments of the Drosophila stage 16 embryonic ventral nerve cord. MAb BP102 (magenta) labels all axons in the central nervous system. egGal4 drives GFP (green) expression in a subset of commissural neurons. FP, floor plate. LF, lateral funiculus. VF, ventral funiculus. AC, anterior commissure. PC, posterior commissure. (a–c: Reprinted with permission from Ref. Copyright 2012 Elsevier)
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