Netrin-1/DCC-mediated PLCγ1 activation is required for axon guidance and brain structure development.

Coordinated expression of guidance molecules and their signal transduction are critical for correct brain wiring. Previous studies have shown that phospholipase C gamma1 (PLCγ1), a signal transducer of receptor tyrosine kinases, plays a specific role in the regulation of neuronal cell morphology and motility in vitro However, several questions remain regarding the extracellular stimulus that triggers PLCγ1 signaling and the exact role PLCγ1 plays in nervous system development. Here, we demonstrate that PLCγ1 mediates axonal guidance through a netrin-1/deleted in colorectal cancer (DCC) complex. Netrin-1/DCC activates PLCγ1 through Src kinase to induce actin cytoskeleton rearrangement. Neuronal progenitor-specific knockout of Plcg1 in mice causes axon guidance defects in the dorsal part of the mesencephalon during embryogenesis. Adult Plcg1-deficient mice exhibit structural alterations in the corpus callosum, substantia innominata, and olfactory tubercle. These results suggest that PLCγ1 plays an important role in the correct development of white matter structure by mediating netrin-1/DCC signaling.