, 2000, Patel et al., 2003 and Tucker et al., 2001). Neurotrophins act through the distinct Trk receptors

activating signaling cascades relayed by the PI3K-Akt and Ras-MAPK signaling pathways, PD0332991 clinical trial which in turn directly regulate cytoskeletal elements modulating actin and microtubule polymerization at the growth cone (Huber et al., 2003 and Zhou and Snider, 2006). However, neurotrophins also induce changes in transcription that are thought to play critical roles in axon growth (Segal and Greenberg, 1996). Accordingly, neurotrophin signaling regulates the transcription factors CREB and NFAT to stimulate axon growth (Graef et al., 2003 and Lonze et al., 2002). Conversely, transcription factors regulate the expression of neurotrophin receptors to specify neuronal subtypes and promote axon growth. For example, the transcription factor Runx1 induces the timely expression of TrkA to promote the specification of nociceptive neurons and growth of their axons (Marmigère et al., 2006). These findings suggest that cell-intrinsic mechanisms orchestrate responses to neurotrophins in the control of axon growth. Several lines of evidence support the concept that the Small molecule library high throughput capacity of a neuron to extend axons

and project to the appropriate targets is intrinsically encoded. Neurons of the peripheral nervous system (PNS), but not the central nervous system (CNS), have the capacity to regenerate axons after injury (Aguayo et al., 1991). The axon growth-inhibiting environment of the adult CNS, chiefly generated

by myelin Org 27569 proteins, contributes to this differential response (Filbin, 2003, He and Koprivica, 2004 and Schwab, 2004). However, the observation that embryonic CNS or adult PNS neurons can extend axons on top of adult white matter suggests that an intrinsic property of neurons in the adult CNS contributes to the failure of axon regeneration after injury (Davies et al., 1997, Davies et al., 1999 and Schwab and Bartholdi, 1996). Consistently, embryonic RGCs have a higher capacity to extend axons than postnatal RGCs, and this change in the capacity of axon growth requires new gene transcription (Moore et al., 2009). Importantly, emerging evidence suggests that the intrinsic axonal growth capacity is regulated by transcription factors, both during development and in the context of injury. Evidence for a cell-intrinsic mechanism regulating axon growth has also emerged from studies of granule neurons of the developing cerebellar cortex. The ubiquitin ligase Cdh1-APC plays a critical role in the control of axon growth and patterning in the rodent cerebellar cortex (Konishi et al., 2004). Knockdown of Cdh1 in primary granule neurons stimulates axon growth even in the presence of the growth-inhibiting environment of myelin. Localization of Cdh1 in the nucleus is required for Cdh1-APC-inhibition of axon growth (Stegmüller et al., 2006).