Abstract
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.
Highlights
During development, several axon guidance molecules act as key regulators of neuronal wiring by inducing cytoskeleton rearrangement [1]
This study showed that PLCc1 may be a potential messenger of netrin-1/deleted in colorectal cancer (DCC) signaling; there is no direct evidence of a relationship between the DCC receptor and PLCc1 because receptor DCC does not contain an intracellular catalytic domain
It is noteworthy that the observed mesencephalic pathway defect in Plcg1f/f;Nes-Cre embryos may stem from disrupted intracellular downstream signaling of the netrin-1/DCC pathway, because a netrin-1/DCC mutation resulted in a malformed mesencephalic pathway [24]
Summary
Several axon guidance molecules act as key regulators of neuronal wiring by inducing cytoskeleton rearrangement [1]. We found that netrin-1/ DCC signaling, a mediator of chemoattractant guidance cues, activates the lipase activity of PLCc1 through proto-oncogene tyrosineprotein kinase Src. Plcg1f/f;Nes-Cre embryos showed a severe axon guidance defect in the dorsal region of the mesencephalon, suggesting that PLCc1 may be involved in axon guidance in midbrain dopaminergic (mDA) neurons. Our results indicate that PLCc1 is a crucial molecule mediating the directional movement of axons that are regulated by netrin-1/ DCC signaling during brain development.
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