The failure of axons to regenerate is a major obstacle for functional recovery after central nervous system (CNS) injury. Removing extracellular inhibitory molecules results in limited axon regeneration in vivo. To test for the role of intrinsic impediments to axon regrowth, we analyzed cell growth control genes using a virus-assisted in vivo conditional knockout approach. Deletion of PTEN (phosphatase and tensin homolog), a negative regulator of the mammalian target of rapamycin (mTOR) pathway, in adult retinal ganglion cells (RGCs) promotes robust axon regeneration after optic nerve injury. In wild-type adult mice, the mTOR activity was suppressed and new protein synthesis was impaired in axotomized RGCs, which may contribute to the regeneration failure. Reactivating this pathway by conditional knockout of tuberous sclerosis complex 1, another negative regulator of the mTOR pathway, also leads to axon regeneration. Thus, our results suggest the manipulation of intrinsic growth control pathways as a therapeutic approach to promote axon regeneration after CNS injury.Axons do not regenerate after injury in the adult mammalian central nervous system (CNS), a phenomenon attributed to two properties of the adult CNS, the inhibitory extrinsic environment and a diminished intrinsic regenerative capacity of mature CNS neurons (1-4). Neutralization of the extracellular molecules identified as axon regrowth inhibitors allows only a limited degree of axon regeneration in vivo (5-7). Therefore, intrinsic mechanisms are likely to be important in controlling the process of axon regeneration. A hint about possible mechanisms of neuronal regenerative ability comes from the evolutionarily conserved molecular pathways that control cellular growth and size. For most cell types, specific mechanisms are necessary to prevent cellular overgrowth upon the completion of development (8). Because many of these molecules are often expressed in postmitotic mature neurons, we hypothesized that they may contribute to the diminished regenerative ability in adult CNS neurons.To circumvent the problem that germline knockout of individual cell growth control genes often results in compromised viability in mice, we designed a strategy based on intravitreal injection of adeno-associated viruses expressing Cre (AAV-Cre) in adult mice. This procedure resulted in the expression of Cre in more than 90% of retinal ganglion cells (RGCs) and few other non-RGC cells, as indicated in two reporter lines ( fig. S1, A and B). We thus injected AAV-Cre into the vitreous body of different adult floxed mice, including Rb f/f (9), P53 f/f (9),

Damage to the adult CNS often leads to persistent deficits due to the inability of mature axons to regenerate after injury. Mounting evidence suggests that the glial environment of the adult CNS, which includes inhibitory molecules in CNS myelin as well as proteoglycans associated with astroglial scarring, might present a major hurdle for successful axon regeneration. Here, we evaluate the molecular basis of these inhibitory influences and their contributions to the limitation of longdistance axon repair and other types of structural plasticity. Greater insight into glial inhibition is crucial for developing therapies to promote functional recovery after neural injury.The nervous system has the remarkable ability to adapt and respond to various stimuli, ranging from physiological experiences associated with learning and memory, to pathological insults such as traumatic injury, stroke or neurodegenerative diseases. In addition to plasticity at the functional level, nervous system responses might also occur in the form of structural remodelling. In vivo imaging studies have shown that sensory experience can drive the formation and elimination of synapses, and that these changes might underlie the adaptive remodelling of neural circuits 1,2 . Similarly, neural injury is often accompanied by a transient period of anatomical remodel ling in the form of local sprouting at the lesion site 3 . However, although many CNS neurons can survive for years after axotomy, the severed axons ultimately fail to regenerate beyond the lesion site, in contrast to those in the PNS or embryonic nervous system. Recent evidence is beginning to reveal intriguing parallels between some of the molecular mechanisms that affect the different forms of structural plasticity, including both short-range remodelling and long-distance axon regrowth. Therefore, targeting these mechanisms might not only promote the regeneration of damaged nerve fibres, but might also enhance axon sprouting and plasticity after CNS injury. Here, we describe recent progress in under standing the inhibitory components of the adult glial environment, as well as the neuronal receptor complexes and downstream signals that mediate their effects. The limited success in targeting these pathways in vivo will then be evaluated. Finally, we discuss the physiological roles of glial inhibition in the intact nervous system, and their implications for the development of strategies to promote functional recovery after adult CNS injury. The role of extrinsic inhibitionThe regeneration failure in the adult CNS might be partly attributed to the gradual decline in the intrinsic growth ability of neurons as the animal matures. Ramón y Cajal described that, © 2006 Nature Publishing Group Correspondence to Z.H. e-mail: E-mail: zhigang.he@childrens.harvard.edu. Competing interests statementThe authors declare no competing financial interests. DATABASES NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript after injury, the ends of lesioned axons become swollen in...

In Drosophila, plexin A is a functional receptor for semaphorin-1a. Here we show that the human plexin gene family comprises at least nine members in four subfamilies. Plexin-B1 is a receptor for the transmembrane semaphorin Sema4D (CD100), and plexin-C1 is a receptor for the GPI-anchored semaphorin Sema7A (Sema-K1). Secreted (class 3) semaphorins do not bind directly to plexins, but rather plexins associate with neuropilins, coreceptors for these semaphorins. Plexins are widely expressed: in neurons, the expression of a truncated plexin-A1 protein blocks axon repulsion by Sema3A. The cytoplasmic domain of plexins associates with a tyrosine kinase activity. Plexins may also act as ligands mediating repulsion in epithelial cells in vitro. We conclude that plexins are receptors for multiple (and perhaps all) classes of semaphorins, either alone or in combination with neuropilins, and trigger a novel signal transduction pathway controlling cell repulsion.