Dendrites actively restrain axon outgrowth and regeneration.

The development of approaches to regenerate neuronal connections that are lost after nervous system injury or during disease has proven enormously challenging. In the mammalian CNS the problem appears to be (at least) twofold. First, local extrinsic cues potently suppress axon outgrowth. However, efforts to blunt growth inhibitory effects of these molecules have not resulted in widespread regrowth of axons after lesion (1). The second problem is that functionally mature neurons, in contrast to developing neurons, appear to have a low intrinsic capacity for growth (2). Preconditioning lesions, where one axonal branch of a neuron is severed, can significantly enhance the outgrowth of other axonal branches in response to subsequent axotomy (3). The effect of the preconditioning lesion has been thought to result from the first lesion driving neuronal de-differentiation and resetting its fate to something more like a developing neuron (4), but the precise mechanisms involved have remained unclear. In PNAS, Chung et al. (5) use an elegant combination of genetics, laser ablations, and pharmacology to demonstrate that dendrites actively repress regenerative outgrowth in functionally mature neurons through a pathway that is independent of the well-conserved dual leucine zipper kinase (DLK)regulated regeneration cascade (Fig. 1). Moreover, this pathway shares important cellular and molecular features with a previously described form of stress-induced ectopic axon outgrowth, suggesting common mechanisms may underlie these processes. Chung et al. (5) investigate sensory regulation of regeneration in Caenorhabditis elegans ASJ sensory neurons. These neurons are bilaterally symmetrical and bipolar: from each ASJ neuronal cell body projects a single dendrite with sensory cilia and an axonal connection to the nerve ring (central ganglion of the nematode nervous system), and each compartment of the cell can be easily resolved by microscopy. Chung et al. use femtosecond laser surgery to sever ASJ axons near the cell soma and demonstrate that regeneration is robust and specific to axons. Following laser axotomy in wild-type, >95% of neurons show significant regeneration. In contrast, dendrite transection results in little to no outgrowth. Prior work has shown that regeneration in a variety of experimental systems is strongly dependent on DLK-1 (6–9). Mutation of dlk-1 also eliminated regeneration after laser cutting of ASJ axons. Surprisingly, however, Chung et al. (5) found that simultaneous cutting of the ASJ axon and dendrite restores the regenerative capacity of ASJ axons even in dlk-1mutants. dendrite soma axon synapse