A human DCC variant causing mirror movement disorder reveals that the WAVE regulatory complex mediates axon guidance by netrin-1–DCC.

The axon guidance cue netrin-1 signals through its receptor DCC (deleted in colorectal cancer) to attract commissural axons to the midline. Variants in DCC are frequently associated with congenital mirror movements (CMMs). A CMM-associated variant in the cytoplasmic tail of DCC is located in a conserved motif predicted to bind to a regulator of actin dynamics called the WAVE (Wiskott-Aldrich syndrome protein–family verprolin homologous protein) regulatory complex (WRC). Here, we explored how this variant affects DCC function and may contribute to CMM. We found that a conserved WRC-interacting receptor sequence (WIRS) motif in the cytoplasmic tail of DCC mediated the interaction between DCC and the WRC. This interaction was required for netrin-1–mediated axon guidance in cultured rodent commissural neurons. Furthermore, the WIRS motif of Fra, the Drosophila DCC ortholog, was required for attractive signaling in vivo at the Drosophila midline. The CMM-associated R1343H variant of DCC, which altered the WIRS motif, prevented the DCC-WRC interaction and impaired axon guidance in cultured commissural neurons and in Drosophila. The findings reveal the WRC as a pivotal component of netrin-1–DCC signaling and uncover a molecular mechanism explaining how a human genetic variant in the cytoplasmic tail of DCC may lead to CMM. Editor's summary: Mirror movements—when intentional movements on one side of the body are mirrored involuntarily on the other side—can occur during normal development and with aging but are also caused by a congenital disorder called CMM. Chaudhari et al. investigated a CMM-associated variant in the axon guidance receptor DCC. They found that the variant disrupted the binding between DCC and the intracellular WAVE regulatory complex, which regulates actin dynamics that are critical for axonal navigation. In flies, neurons expressing the variant or a mutant lacking the WAVE-binding region failed to extend axons properly to and across the body midline, demonstrating how the variant may underlie CMM. —Leslie K. Ferrarelli [ABSTRACT FROM AUTHOR]