In order to orchestrate an integrated response to axonal injury, JNK activity not only is necessary and sufficient for growth cone dynamics and axonal extension, but also interacts with other molecular signals including amyloid precursor protein (APP), the dual leucine zipper-containing kinase (DLK)/Wallenda (Wnd), and the cAMP-PKA pathway (Fang and Bonini, 2012)

In order to orchestrate an integrated response to axonal injury, JNK activity not only is necessary and sufficient for growth cone dynamics and axonal extension, but also interacts with other molecular signals including amyloid precursor protein (APP), the dual leucine zipper-containing kinase (DLK)/Wallenda (Wnd), and the cAMP-PKA pathway (Fang and Bonini, 2012). vertebrate and invertebrate CNS, neurons have limited capacity to grow upon damage, revealing a combination of poor regenerative capacity with a discouraging cellular environment. Therefore , knowing more about the molecular pathways that modulate axonal regeneration can yield promising targets in the treatment of human neurodegeneration and CNS injuries. A major goal in CNS regenerative research is to develop strategies to re-establish the lost innervation. Remarkably, many of the molecular players involved in regeneration also participate in axonal growth and guidance during embryonic development. This emphasises the crucial importance of increasing the current knowledge on the molecular pathways involved in axonal growth and guidance and be able to draw parallels with axonal regeneration. To know more about axonal growth and guidance and their links to regeneration, model organisms, like the fruit fly, Drosophila melanogaster, are of foremost importance. Sequencing of the human genome has and will accelerate the identification of many genes and the molecular processes involved in human diseases. In order to understand the molecular and cellular pathways involved in human pathologies, these can be modeled in easily manageable model organisms likeDrosophila. The power of this genetic system has revealed many TAB29 genetic factors involved in various pathways affected in genetic and acquired human diseases, as well as provided potential drug targets for therapeutics. Drosophilais a well-established model, ideal for forward and reverse genetics experiments andin vivostudies. The evolutionary conservation of gene function between humans andDrosophilamake it an ideal model system with great applicability in the study of human pathologies. To this we must add the great and detailed knowledge gathered over the past century on the biology and genetics of this organism. Many aspects of human disease are also found in flies. These include cancer, ageing, neurodegeneration, infectious diseases, and dysfunction of neurotransmitter and endocrine systems (Lessing and Bonini, 2009). Interestingly, a number of inherited human neurodegenerative diseases have been successfully TAB29 modelled inDrosophila(Lessing and Bonini, 2009) and both larvae and adult flies are good models for axonal injury and regeneration TAB29 (Ayaz et al., 2008). Similar to their mammalian homologues, fly CNS neurons respond to injury by transient upregulation of the stress response c-Jun N-terminal protein kinase (JNK) pathway Esm1 (Leyssen et al., 2005) and by Wallerian degeneration of their axons (MacDonald et al., 2006). In addition , as in vertebrates, Drosophilanerve tracts are typically comprised of many axons, which, although lacking myelin, are ensheathed by glial cells (MacDonald et al., 2006). Finally, Drosophilaaxons are able to undergo new axonal growth after injury, and genetic studies indicate that conserved signalling molecules are required for this process (Ayaz et al., 2008; Xiong et al., 2010). For an axon to regenerate, it needs to go through many processes that resemble axonal embryonic development. Namely, it needs to form a growth cone, grow and extend in the appropriate direction and finally find its innervation targets. However , in human nerve regeneration, these processes mostly happen many years or even decades after the nervous system was developing. Following embryonic nervous system development, expression patterns of many axon guidance molecules are reduced, or at least changed. Others keep their embryonic expression levels and are still abundantly present in the mature CNS. The presence of these molecules in the adult nervous system suggests other roles for guidance cues beyond the initial phase of axonal outgrowth, growth cone navigation, and target innervation. And even though after embryogenesis, neuronal circuits become more stable, it is also important to highlight that adult nervous system connectivity is not hardwired. Indeed, plasticity endures all throughout adulthood in response to experience, injury, and ageing. This plasticity needs to be molecularly modulated. Because many mature neurons still express receptors for guidance cues, it has been speculated that these may continue to play a role in TAB29 adulthood. Several axon guidance molecules including Semaphorins, Ephrins, Wnts, Slits, and Netrins become upregulated in the vertebrate adult CNS after injury (Giger et al., 2010). They are obvious candidates for modulating the growth of axons in the adult. Thus, these guidance factors have received much attention in regenerative studies. Growth cones and the cytoskeleton: Leading to successful nerve regeneration, one of the first steps after physical injury of the axon is the formation of a new growth cone. This is achieved through the reorganization of the cytoskeleton at the proximal axonal stump. Growth-cone formation and its.