Recapitulate development to promote axonal regeneration: good or bad approach?

Abstract

In the past decade there has been an explosion in our understanding, at the molecular level, of why axons in the adult, mammalian central nervous system (CNS) do not spontaneously regenerate while their younger counterparts do. Now a number of inhibitors of axonal regeneration have been described, some of the receptors they interact with to transduce the inhibitory signal are known, as are some of the steps in the signal transduction pathway that is responsible for inhibition. In addition, developmental changes in the environment and in the neurons themselves are also now better understood. This knowledge in turn reveals novel, putative sites for drug development and therapeutic intervention after injury to the brain and spinal cord. The challenge now is to determine which of these putative treatments are the most effective and if they would be better applied in combination rather than alone. In this review I will summarize what we have learnt about these molecules and how they signal. Importantly, I will also describe approches that have been shown to block inhibitors and encourage regeneration in vivo. I will also speculate on what the differences are between the neonatal and adult CNS that allow the former to regenerate and the latter not to.

Disease Gene Candidates Revealed by Expression Profiling of Retinal Ganglion Cell Development

“…An important question is whether regenerative axon growth programs recapitulate developmental axon growth programs and whether such a recapitulation would enhance regenerative response (Filbin, 2006). Although RGCs decrease their intrinsic axon growth capacity through development, correlating with a failure of regenerative response in vivo, certain treatments such as Rho inactivation, CNTF plus cAMP application, and lens injury are able to enhance the regenerative response of RGCs in vivo (Leon et al, 2000;Cui et al, 2003;Yin et al, 2003Yin et al, , 2006Fischer et al, 2004).…”

Heterogeneous Nuclear Ribonucleoprotein K, an RNA-Binding Protein, Is Required for Optic Axon Regeneration inXenopus laevis

“…hnRNP K directly binds both GAP-43 and NF-M RNAs (Irwin et al, 1997;Thyagarajan and Szaro, 2004;Liu and Szaro, 2011), but whether it regulates their expression during optic axon regeneration is unclear, since factors controlling expression of these genes can be distinct as well as shared between development and regeneration (Udvadia et al, 2001;Filbin, 2006;Kusik et al, 2010). Using a novel in vivo method to suppress its expression specifically in RGCs, we show here that hnRNP K is essential in Xenopus both for optic axon regeneration and for the efficient nuclear export and translation of growth-associated transcripts bound by hnRNP K. Thus, hnRNP K is an element of a novel posttranscriptional regulatory pathway essential for successful CNS axon regeneration.…”

Regeneration ofDrosophilasensory neuron axons and dendrites is regulated by the Akt pathway involvingPtenand microRNAbantam

“…Received March 30, 2012;revised version accepted May 29, 2012. Damage to the adult CNS often leads to persistent deficits due to the inability of axons to regenerate after injury, which may reflect an inhibitory extrinsic environment and a diminished intrinsic regenerative capacity (Schwab and Bartholdi 1996;Goldberg et al 2002;Filbin 2006;Fitch and Silver 2008). Whereas CNS axon regeneration may be impeded by inhibitory molecules associated with the myelin debris (e.g., MAG, Nogo-A, and OMgp) or with glial scar formation (e.g., CSPG and tenasin) (Yiu and He 2006;Sun and He 2010), eliminating these molecules only allows limited sprouting in vivo (Case and TessierLavigne 2005;Harel and Strittmatter 2006;Yiu and He 2006;Sun and He 2010).…”