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 corticosp inal tract (CST), a pathway controlling voluntary movements, and of the ant erior commissure (AC), connecting the neocortical temporal robes. To study EphA4 kinase signaling in these processes, we generated mice expressing mut ant EphA4 receptors either lacking kinase activity or with severely downreg ulated kinase activity. We demonstrate that EphA4 is required for CST forma tion as a receptor for which it requires an active kinase domain. In contra st, the formation of the AC is rescued by kinase-dead EphA4, suggesting tha t in this structure EphA4 acts as a ligand for which its kinase activity is not required. Unexpectedly, the cytoplasmic sterile-alpha motif (SAM) doma in is not required for EphA4 functions. Our findings establish both kinase- dependent and kinase-independent functions of EphA4 in the formation of maj or axon tracts.