In the developing brain, commissural axons from one hemisphere extend and connect with neurons in the other hemisphere, enabling the coordination of various cognitive, motor, and behavioral functions. After crossing the midline, axons are sent away from the midline by repulsive guidance cues, such as Semaphorin-3B, which signals through the PlexinA1/Neuropilin receptor complex, and the N-terminal fragment of Slit, which signals through the receptors of the Robo family. Delloye-Bourgeois et al. injected a fluorescent dye and monitored commissural axon trajectories in developing mouse embryos. Axons in PlxnA1 or Sema3B single-knockout mouse embryos or Robo1/Robo2 double-knockout mouse embryos stalled and turned back toward the midline. However, axons in the PlxnA1 knockouts or in PlxnA1/Robo1/Robo2 triple knockouts recrossed the midline, which is similar to that observed previously in Slit knockouts. Furthermore, deleting one copy of PlxnA1 increased the recrossing phenotype in Slit heterozygote embryos. Independently of Robo, full-length Slit and C-terminal (SlitC) but not N-terminal of Slit (SlitN) coimmunoprecipitated with PlexinA1 in mouse embryonic spinal cord lysates, extracted mouse commissural tissue, and transfected COS7 cells. Adding SlitC to cultures of wild-type or Robo-deficient but not PlexinA1-deficient commissural neurons triggered axon growth cone collapse. In transfected COS7 cells, SlitC activated PlexinA1 and associated downstream signaling events, similar to those produced by Semaphorin-3B. However, unlike Semaphorin-3B–induced signaling, the coreceptor Neuropilin-2 was dispensible to SlitC-PlexinA1 signaling in growth cone collapse. Together, the findings identify a distinct functional target for the C-terminal fragment of Slit that complements the role of its N-terminal fragment in the developing brain.
C. Delloye-Bourgeois, A. Jacquier, C. Charoy, F. Reynaud, H. Nawabi, K. Thoinet, K. Kindbeiter, Y. Yoshida, Y. Zagar, Y. Kong, Y. E. Jones, J. Falk, A. Chédotal, V. Castellani, PlexinA1 is a new Slit receptor and mediates axon guidance function of Slit C-terminal fragments. Nat. Neurosci.18, 36–45 (2015). [PubMed]