The study of neuronal polarization is relevant beyond the context of brain development. Spinal cord injury presents a scenario where neurons have to regrow axons from an axonal stump. Axon transection can lead to the respecification of a dendrite into an axon (Bradke and Dotti, 2000, Gomis-Rüth et al.,

2008, Goslin and Banker, 1989 and Takahashi et al., 2007). In particular, depending on the proximity of the injury to the soma, neurons either extend an axon from the original stump or from a dendrite (Gomis-Rüth et al., 2008). These studies suggest that neuronal polarity is plastic, and conversely the polarized state is actively maintained by dedicated mechanisms (Bisbal et al., 2008, Hedstrom et al., 2008, Jiang et al., 2005, Kobayashi et al., 1992, Nakada et al., 2003, Winckler et al., 1999 and Yin et al., 2008). Thus, regulators of neuronal polarity http://www.selleckchem.com/products/PD-0325901.html Saracatinib order might influence axon regeneration by directing axon re-specification and

extension. In this regard, it will be important to determine if FOXO-dependent transcription is required for axon regeneration and in particular whether activators of FOXO proteins can accelerate axon growth after injury. Along these lines, increased SIRT1 activity is associated with protection of dorsal root ganglion (DRG) axons from Wallerian degeneration (Araki et al., 2004). In light of the observation that SIRT1-induced deacetylation of FOXO proteins stimulates FOXO-dependent transcription (Brunet et al.,

2004 and Daitoku et al., 2004), the FOXO proteins might mediate the protective effect of SIRT1 against axon degeneration. Because the FOXO proteins are regulated by distinct signaling pathways in response to cellular stress, including the protein kinase JNK which stimulates Phosphoprotein phosphatase axon regeneration after injury (Lindwall et al., 2004), the FOXO proteins are ideally positioned to promote axon regeneration after injury. Several classes of neurons, including projection neurons in the cerebral cortex must extend axons over very long distances in a stereotyped path to innervate specific targets. Beyond the fundamental question of how neurons accomplish this monumental task during development, understanding the mechanisms that promote axon growth may form the basis of treatments aimed at recovery in the central nervous system following injury or disease. The role of extrinsic cues, including neurotrophic factors, in promoting axon elongation is compelling. Exposure of distinct populations of primary neurons, including retinal ganglion cells, DRG neurons, and hippocampal neurons to NGF, BDNF, or NT-3 promotes axon growth robustly (Goldberg et al., 2002a, Lentz et al., 1999, Markus et al., 2002b and Shinoda et al., 2007). Importantly, a requirement for neurotrophin signaling in normal axon development has been validated in vivo (Glebova and Ginty, 2004, Kuruvilla et al.