Cell adhesion molecules (CAMs) regulate neural development via both homophilic and heterophilic binding interactions. Various members of the receptor protein tyrosine phosphatase (RPTP) subfamily of CAMs mediate neurite outgrowth, yet in many cases, their ligands remain unknown. However, the PTP mu subfamily members are homophilic binding proteins. PTP mu is a growth-permissive substrate for nasal retinal ganglion cell (RGC) neurites and a growth inhibitory substrate for temporal RGC neurites. Whether PTP mu regulates these distinct behaviors via homophilic or heterophilic binding interactions is not currently known. In this manuscript, we demonstrate that PTP mu influences RGC axon guidance behaviors only in the E8 retina and not earlier in development. In addition, we demonstrate that PTP mu is permissive only for neurites from ventral-nasal retina and is repulsive to neurites from all other retinal quadrants. Furthermore, we show that PTP mu-mediated nasal neurite outgrowth and temporal repulsion require PTP mu expression and catalytic activity. These results are consistent with PTP mu homophilic binding generating a tyrosine phosphatase-dependent signal that ultimately leads to axon outgrowth or repulsion and that PTP mu's role in regulating axon guidance may be tightly regulated developmentally. In summary, these data demonstrate that PTP mu expression and catalytic activity are important in vertebrate axon guidance.
