A tug of war between DCC and ROBO1 signaling during commissural axon guidance

Dynamic and coordinated axonal responses to changing environments are critical for establishing neural connections. As commissural axons migrate across the CNS midline, they are suggested to switch from being attracted to being repelled in order to approach and to subsequently leave the midline. A molecular mechanism that is hypothesized to underlie this switch in axonal responses is the silencing of Netrin1/Deleted in Colorectal Carcinoma (DCC)-mediated attraction by the repulsive SLIT/ROBO1 signaling. Using in vivo approaches including CRISPR-Cas9-engineered mouse models of distinct Dcc splice isoforms, we show here that commissural axons maintain responsiveness to both Netrin and SLIT during midline crossing, although likely at quantitatively different levels. In addition, full-length DCC in collaboration with ROBO3 can antagonize ROBO1 repulsion in vivo. We propose that commissural axons integrate and balance the opposing DCC and Roundabout (ROBO) signaling to ensure proper guidance decisions during midline entry and exit. [Display omitted] •Two DCC receptor isoforms are required to achieve proper Netrin1 signaling in vivo•DCCL and DCCS adopt different conformations and have distinct signaling abilities•Solely expressing DCCL or DCCS alters axon growth, attraction, and fasciculation•Netrin1/DCCL together with ROBO3.1 antagonizes Slit/ROBO1 signaling Using CRISPR-Cas9-engineered Dcc isoform mutants, Dailey-Krempel et al. show that Netrin1/DCC and SLIT/ROBO1 signaling are engaged in a counteraction akin to a tug of war in regulating axon guidance in vivo.