The neural adhesion molecule TAG-1 modulates responses of sensory axons to diffusible guidance signals.
When the axons of primary sensory neurons project into the embryonic mammalian spinal cord, they bifurcate and extend rostrocaudally before sending collaterals to specific laminae according to neuronal subclass. The specificity of this innervation has been suggested to be the result both of differential sensitivity to chemorepellants expressed in the ventral spinal cord and of the function of Ig-like neural cell adhesion molecules in the dorsal horn. The relationship between these mechanisms has not been addressed. Focussing on the pathfinding of TrkA+ NGF-dependent axons, we demonstrate for the first time that their axons project prematurely into the dorsal horn of both L1 and TAG-1 knockout mice. We show that axons lacking TAG-1, similar to those lacking L1, are insensitive to wild-type ventral spinal cord (VSC)-derived chemorepellants, indicating that adhesion molecule function is required in the axons, and that this loss of response is explained in part by loss of response to Sema3A. We present evidence that TAG-1 affects sensitivity to Sema3A by binding to L1 and modulating the endocytosis of the L1/neuropilin 1 Sema3A receptor complex. However, TAG-1 appears to affect sensitivity to other VSC-derived chemorepellants via an L1-independent mechanism. We suggest that this dependence of chemorepellant sensitivity on the functions of combinations of adhesion molecules is important to ensure that axons project via specific pathways before extending to their final targets.
Law
Chris O
CO
Department of Biomedical Science, University of Sheffield, Western Bank, Sheffield, UK.
Kirby
Rebecca J
RJ
Aghamohammadzadeh
Soheil
S
Furley
Andrew J W
AJ
D000483:Alleles; D000818:Animals; D001369:Axons / Q000502:physiology*; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism*; D058969:Contactin 2; D004058:Diffusion; D004705:Endocytosis / Q000502:physiology; D020439:Growth Cones / Q000502:physiology; D039841:Leukocyte L1 Antigen Complex / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009154:Mutation; D019006:Neural Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D009475:Neurons, Afferent / Q000166:cytology / Q000378:metabolism*; D040121:Semaphorin-3A / Q000378:metabolism
D015816:Cell Adhesion Molecules, Neuronal; C548675:Cntn2 protein, mouse; D058969:Contactin 2; D039841:Leukocyte L1 Antigen Complex; D019006:Neural Cell Adhesion Molecules; D040121:Semaphorin-3A