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Genetic and molecular analysis of axon guidance during embryonic development
AuthorShoja Taheri, Farnaz
AdvisorMastick, Grant S.
Biochemistry and Molecular Biology
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Axon guidance is fundamental for the neuronal wiring and the organization of the nervous system. Formation of the neuronal networks occurs through precise projections of axons to their final destinations by responding to various attractive and repulsive guidance cues in their environment. It is important to understand how the integration of various guidance signals occurs inside the growth cone and how the growth cone makes the correct decision to reach the final target. Netrin1 and Slit signalings are two important guidance signals that are required for the proper navigation of several neuronal populations, including commissural axons. Commissural axons project toward and across the ventral midline using Netrin1 activation of DCC. After crossing the midline, axons lose their responsiveness to Netrin1 and become sensitive to Slit–Robo repulsion. The switch in responses occurs through a Slit silencing mechanism, in which Slits signal through their Robo receptors for repulsion, but in the same time Robos bind to DCC and block DCC–mediated Netrin1 attraction. This switch provides a condition for commissural axons to avoid lingering in or recrossing the midline. Longitudinal trajectories of post–crossing commissural axons navigate at distinct distances from the midline and their position is maintained parallel to the midline for long distances. The trajectory of post–crossing axons is reminiscent of longitudinal axons. Longitudinal axons use a balance of positive and negative cues from the midline for their guidance. To determine if similar to longitudinal axons, Netrin1–DCC signaling remains active in post–crossing longitudinal trajectories, we used mouse embryos mutant for Netrin1. Hindbrain post–crossing axons projected abnormally at angles away from the midline, suggesting the involvement of Netrin1 attraction in the guidance of these trajectories. Ectopic expression of Netrin1 was also sufficient to cause attractive deflection of post–crossing axons. However, analysis of Robo1/2 mutants showed that Slit–Robo repulsive signaling was not required for the guidance of these axons. Taken together, our findings suggest that Netrin1–DCC attractive signaling, but not Slit–Robo repulsive signaling, remains active in hindbrain post–crossing commissural axons to guide longitudinal trajectories.In an unrelated study, we aimed to introduce a novel guidance cue–receptor complex in vertebrates: Chordin–DSCAM. To investigate the function of DSCAM and Chordin, the spatiotemporal expression patterns of DSCAM and Chordin were examined in the developing mouse central nervous system. DSCAM expression was detected in a subset of longitudinal axons, motor columns and commissural axons, while Chordin expression was observed in a subset of motor neurons, commissural neurons, and the ventral half of the neural tube. The expression of both DSCAM and Chordin was also detected in the cortex and cerebellum of older embryos. Chordin was expressed in a pattern suggestive of an axon guidance cue for DSCAM+ axons. To determine the physiological effect of Chordin on DSCAM+ axons, we exposed cultured MLF (Medial Longitudinal Fascicle), MN, and commissural axons to Chordin and found increased outgrowth only in MLF axons. Our findings suggest that Chordin may function as a novel axon guidance cue on a range of different types of neurons, and this function could be carried out in a DSCAM–dependent or –independent manner.