Rac1 and Nectin3 are essential for PCP-directed axon guidance in the peripheral auditory system.

Planar Cell Polarity (PCP) signaling plays a non-autonomous role in the guidance of type II spiral ganglion neuron (SGNII) afferent projections that innervate cochlear hair cells. However, little is known about the underlying mechanisms. Here, we identify the small GTPase Rac1 and the cell adhesion molecule Nectin3 as two downstream effectors of PCP signaling in SGNII afferent guidance. We show that PCP signaling regulates Rac1 and Nectin3 localization in cochlear supporting cells that serve as intermediate targets for SGNII afferents and that Rac1 and Nectin3 likely act in the same genetic pathway to non-autonomously regulate SGNII afferent guidance. These findings significantly advance our understanding of auditory circuit assembly and shed light on PCP-directed axon guidance mechanisms.