Analysis of the L1-deficient mouse phenotype reveals cross-talk between Sema3A and L1 signaling pathways in axonal guidance.
In humans, defects of the corticospinal tract have been attributed to mutations in the gene encoding L1 CAM, a phenotype that is reproduced in L1-deficient mice. Using coculture assays, we report that Sema3A secreted from the ventral spinal cord repels cortical axons from wild-type but not from L1-deficient mice. L1 and neuropilin-1 (NP-1) form a stable complex, and their extracellular domains can directly associate. Thus, L1 is a component of the Sema3A receptor complex, and L1 mutations may disrupt Sema3A signaling in the growth cone, leading to guidance errors. Addition of soluble L1Fc chimeric molecules does not restore Sema3A responsiveness of L1-deficient axons; instead, it converts the repulsion of wild-type axons into an attraction, further supporting a function for L1 in the Sema3A transducing pathways within the growth cone.
Castellani
V
V
Laboratoire de Génétique et Physiologie du Développement, UMR 6545 CNRS, IBDM, Marseille, France.
Chédotal
A
A
Schachner
M
M
Faivre-Sarrailh
C
C
Rougon
G
G
D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism*; D002450:Cell Communication / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D018920:Coculture Techniques; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects; D006023:Glycoproteins / Q000378:metabolism* / Q000494:pharmacology; D020439:Growth Cones / Q000187:drug effects / Q000378:metabolism; D039841:Leukocyte L1 Antigen Complex; D046911:Macromolecular Substances; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D019006:Neural Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D039942:Neuropilin-1; D011233:Precipitin Tests; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology; D040121:Semaphorin-3A; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013116:Spinal Cord / Q000166:cytology / Q000378:metabolism
D006023:Glycoproteins; D039841:Leukocyte L1 Antigen Complex; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules; D011993:Recombinant Fusion Proteins; D040121:Semaphorin-3A; D039942:Neuropilin-1