Disruption of the Frizzled3 (Fz3) gene leads to defects in axonal growth in the VIIth and XIIth cranial motor nerves, the phrenic nerve, and the dorsal motor nerve in fore- and hindlimbs. In Fz3−/− limbs, dorsal axons stall at a precise location in the nerve plexus, and, in contrast to the phenotypes of several other axon path-finding mutants, Fz3−/− dorsal axons do not reroute to other trajectories. Affected motor neurons undergo cell death 2 days prior to the normal wave of developmental cell death that coincides with innervation of muscle targets, providing in vivo evidence for the idea that developing neurons with long-range axons are programmed to die unless their axons arrive at intermediate targets on schedule. These experiments implicate planar cell polarity (PCP) signaling in motor axon growth and they highlight the question of how PCP proteins, which form cell–cell complexes in epithelia, function in the dynamic context of axonal growth.
For the nervous system to become wired up correctly, neurons within the developing embryo must project over long distances to form connections with remote targets. They do this by lengthening their axons—the ‘cables’ along which electrical signals flow—and some axons in adult humans can grow to be more than 1 metre long.
This type of long-range pathfinding activity is particularly common for neurons that control movement, as many of these neurons must establish connections with muscles that are some distance away from the brain. For example, motor neurons in the brainstem form connections with muscles in the face to control facial expressions, while motor neurons in parts of the spinal cord project to muscles in the limbs. Multiple signaling pathways tell the developing axons which direction to grow en route to their final targets.
Now, Hua et al. have shown that an evolutionarily conserved protein called Frizzled3 is also involved in this process. In mouse embryos that lacked Frizzled3, the motor nerves that control breathing and limb movements were thinner than those in normal mice. In the mutant animals, many motor axons failed to form connections with their targets. Instead, these axons came to an abrupt halt midway along their intended paths and the neurons from which they originated died soon afterwards. These experiments support the idea that developing neurons are programmed to die unless their axons progress on the appropriate schedule.
As well as increasing our knowledge of the networks of connections that form within the developing mammalian nervous system, the work of Hua et al. provides new insights into some of the molecular mechanisms by which these connections are established.