No abstract

Failure of severed adult CNS axons to regenerate could be attributed to both a reduced intrinsic capacity to grow and an heightened susceptibility to inhibitory factors of the CNS extracellular environment. A particularly interesting and useful paradigm for investigating CNS axonal regeneration is its enhancement at the CNS branch of dorsal root ganglion (DRG) neurons after conditional lesioning of their peripheral branch. Recent reports have implicated the involvement of two well-known signaling pathways utilizing separate transcription factors; the Cyclic AMP (cAMP) response element binding protein (CREB) and signal transducer and activator of transcription 3 (STAT3), in conditional lesioning. The former appears to be the pathway activated by neurotrophic factors and Bcl-2, while the latter is responsible for the neurogenic effect of cytokines [such as the leukemia inhibitory factor (LIF) and interleukin-6 (IL-6) elevated at lesion sites]. Recent findings also augmented earlier notions that modulations of the activity of another class of cellular signaling intermediate, the conventional protein kinase C (PKC), could result in a contrasting growth response by CNS neurons to myelin-associated inhibitors. We discuss these signaling pathways and mechanisms, in conjunction with other recent reports of regeneration enhancement and also within the context of what is known about aiding regeneration of injured CNS axons. That axons of the adult CNS regenerate poorly after injury is the underlying reason for the devastation associated with physical or ischemic injuries to the brain and spinal cord. Other than the presence of CNS growth inhibitors (Filbin 2003;Sandvig et al. 2004), this poor regenerative capacity may be attributed to a lack of access to neurotrophic factors in the adult CNS. However, exogenous supplementation of injured CNS neurons with neurotrophins, with some exceptions (Ramer et al. 2000), had largely resulted in a limited enhancement of regeneration. Adult CNS neurons are known to be intrinsically poor in regeneration compared to the same neurons at an embryonic stage of development. Embryonic neurons are not simply more vigorous in terms of neurite outgrowth, but also more responsive to neurotrophic stimuli and most importantly, react differently to myelin-associated inhibitors. All these phenomena are readily observed in models of CNS neuron regeneration such as neurons of the dorsal root ganglia (DRG), cerebellar neurons and retinal ganglion cells (RGCs).Below, recent updates to the myriad of molecules, signaling pathways and signaling mechanisms involved in CNS axonal regeneration shall be discussed. It should be kept in mind that signaling events and processes in the regeneration of post-mitotic neurons represent a counterbalance and integration of intrinsic growth ability of the injured neuron (aided or enhanced by signals coming from various neurotrophic factors) and growth inhibitory signals from the CNS environment (such as those from the myelin-associated inhibitors). Much of the ne...

We report Nogo-A as an oligodendroglial component congregating and interacting with the Caspr±F3 complex at paranodes. However, its receptor Nogo-66 receptor (NgR) does not segregate to speci®c axonal domains. CHO cells cotransfected with Caspr and F3, but not with F3 alone, bound speci®cally to substrates coated with Nogo-66 peptide and GST±Nogo-66. Binding persisted even after phosphatidylinositolspeci®c phospholipase C (PI-PLC) removal of GPIlinked F3 from the cell surface, suggesting a direct interaction between Nogo-66 and Caspr. Both Nogo-A and Caspr co-immunoprecipitated with Kv1.1 and Kv1.2, and the developmental expression pattern of both paralleled compared with Kv1.1, implicating a transient interaction between Nogo-A±Caspr and K + channels at early stages of myelination. In pathological models that display paranodal junctional defects (EAE rats, and Shiverer and CGT ±/± mice), distances between the paired labeling of K + channels were shortened signi®cantly and their localization shifted toward paranodes, while paranodal Nogo-A congregation was markedly reduced. Our results demonstrate that Nogo-A interacts in trans with axonal Caspr at CNS paranodes, an interaction that may have a role in modulating axon±glial junction architecture and possibly K + -channel localization during development.

The gene mutated in the mouse open brain (opb) phenotype antagonizes sonic hedgehog-mediated signaling and encodes a small GTPase of the Rab family, Rab23. To date, the brain expression profile and exact mechanism of function of the Rab23 protein has remained unknown. Specific antibodies generated against Rab23 showed that the protein is highly enriched in the adult rodent brain and present in low levels in multiple tissues of the adult rodent. Rab23 is found in the cytosol as well as being associated with the plasma and endosomal membranes. In the adult mouse brain, Rab23 is found in betaIII tubulin (TuJ) positive neuronal cell bodies and are most prominent in the cortex, hypothalamus and the cerebellum. It is, however, absent from glial fibrillary acidic protein (GFAP) positive astrocytes or CNPase positive oligodendrocytes. Despite the plasma membrane/endosomal membrane localization of Rab23, neither overexpression of the GTP-restricted nor the GDP-bound mutant forms affect internalization of transferrin or epidermal growth factor. Exogenous overexpression of Rab23 or its mutants also did not affect the morphological differentiation of thalamic neurons in culture. Expression of Rab23 in the adult brain is suggestive, however, of having a postnatal function beyond its role in embryonic development.

Multipotent adult stem cells capable of developing into particular neuronal cell types have great potential for autologous cell replacement therapy for central nervous system neurodegenerative disorders and traumatic injury. Bone marrow-derived stromal mesenchymal stem cells (BMSCs) appear to be attractive starting materials. One question is whether BMSCs could be coaxed to differentiate in vitro along neuronal or glial lineages that would aid their functional integration post-transplantation, while reducing the risk of malignant transformation. Recent works suggest that BMSCs could indeed be differentiated in vitro to exhibit some cellular and physiological characteristics of neural cell lineages, but it is not likely to be achievable with simple chemical treatments. We discussed recent findings pertaining to efforts in neuronal differentiation of BMSCs in vitro, and results obtained when these were transplanted in vivo.