Semaphorin3D regulates axon axon interactions by modulating levels of L1 cell adhesion molecule.
The decision of a growing axon to selectively fasciculate with and defasciculate from other axons is critical for axon pathfinding and target innervation. Fasciculation can be regulated by cell adhesion molecules that modulate interaxonal adhesion and repulsive molecules, expressed by surrounding tissues that channel axons together. Here we describe crosstalk between molecules that mediate these mechanisms. We show that Semaphorin3D (Sema3D), a classic repulsive molecule, promotes fasciculation by regulating L1 CAM levels and axon-axon interactions rather than by creating a repulsive surround. Knockdown experiments show that Sema3D and L1 genetically interact to promote fasciculation. Sema3D overexpression increases and Sema3D knockdown decreases levels of axonal L1 protein. Moreover, excess L1 rescues defasciculation caused by the loss of Sema3D. In vivo time-lapse imaging reveals that Sema3D or L1 knockdown cause identical defects in growth cone behaviors during axon-axon interactions, consistent with a loss of adhesion. These results reveal a novel mechanism by which a semaphorin promotes fasciculation and modulates axon-axon interactions by regulating an adhesion molecule.
Wolman
Marc A
MA
Department of Zoology, University of Wisconsin, Madison, Wisconsin 53706, USA.
Regnery
Ann M
AM
Becker
Thomas
T
Becker
Catherina G
CG
Halloran
Mary C
MC
D000818:Animals; D030801:Animals, Genetically Modified; D001369:Axons / Q000378:metabolism / Q000502:physiology*; D004625:Embryo, Nonmammalian; D015870:Gene Expression / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000235:genetics; D020439:Growth Cones / Q000187:drug effects / Q000378:metabolism; D009414:Nerve Growth Factors / Q000235:genetics / Q000502:physiology*; D039842:Neural Cell Adhesion Molecule L1 / Q000235:genetics / Q000378:metabolism*; D039942:Neuropilin-1 / Q000235:genetics / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D012249:Rhombencephalon / Q000196:embryology / Q000378:metabolism; D039961:Semaphorins / Q000235:genetics / Q000502:physiology*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000502:physiology*