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

Abstract

Coordinated expression of guidance molecules and their signal transduction are critical for correct brain wiring. Previous studies have shown that phospholipase C gamma1 (PLC gamma 1), 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 PLC gamma 1 signaling and the exact role PLC gamma 1 plays in nervous system development. Here, we demonstrate that PLC gamma 1 mediates axonal guidance through a netrin-1/deleted in colorectal cancer (DCC) complex. Netrin-1/DCC activates PLC gamma 1 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 PLC gamma 1 plays an important role in the correct development of white matter structure by mediating netrin-1/DCC signaling.