Kinase-dependent and kinase-independent functions of EphA4 receptors in major axon tract formation in vivo.
The EphA4 receptor tyrosine kinase regulates the formation of the corticospinal tract (CST), a pathway controlling voluntary movements, and of the anterior commissure (AC), connecting the neocortical temporal lobes. To study EphA4 kinase signaling in these processes, we generated mice expressing mutant EphA4 receptors either lacking kinase activity or with severely downregulated kinase activity. We demonstrate that EphA4 is required for CST formation as a receptor for which it requires an active kinase domain. In contrast, the formation of the AC is rescued by kinase-dead EphA4, suggesting that in this structure EphA4 acts as a ligand for which its kinase activity is not required. Unexpectedly, the cytoplasmic sterile-alpha motif (SAM) domain is not required for EphA4 functions. Our findings establish both kinase-dependent and kinase-independent functions of EphA4 in the formation of major axon tracts.
Kullander
K
K
European Molecular Biology Laboratory, Meyerhofstrasse 1, D-69117, Heidelberg, Germany.
Mather
N K
NK
Diella
F
F
Dottori
M
M
Boyd
A W
AW
Klein
R
R
D000818:Animals; D001369:Axons / Q000201:enzymology*; D001933:Brain Stem / Q000166:cytology / Q000196:embryology / Q000201:enzymology; D036385:Ephrin-A4; D036388:Ephrin-B2; D005326:Fetal Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017403:In Situ Hybridization; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009044:Motor Cortex / Q000166:cytology / Q000196:embryology / Q000201:enzymology; D009928:Organ Specificity; D016548:Prosencephalon / Q000166:cytology / Q000196:embryology / Q000201:enzymology; D017434:Protein Structure, Tertiary / Q000235:genetics; D011712:Pyramidal Tracts / Q000166:cytology / Q000196:embryology* / Q000201:enzymology*; D012333:RNA, Messenger / Q000096:biosynthesis; D020794:Receptor Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D036122:Receptor, EphA4; D015398:Signal Transduction / Q000235:genetics; D013702:Temporal Lobe / Q000166:cytology / Q000196:embryology
D036385:Ephrin-A4; D036388:Ephrin-B2; D005326:Fetal Proteins; D008565:Membrane Proteins; D012333:RNA, Messenger; D020794:Receptor Protein-Tyrosine Kinases; D036122:Receptor, EphA4