Unlike immature neurons and the ones from the peripheral nervous system (PNS), mature neurons from the central nervous system (CNS) cannot regenerate after injury. In the past 15 years, tremendous progress has been made to identify molecules and pathways necessary for neuroprotection and/or axon regeneration after CNS injury. In most regenerative models, phosphorylated ribosomal protein S6 (p-RPS6) is up-regulated in neurons, which is often associated with an activation of the mTOR (mammalian target of rapamycin) pathway. However, the exact contribution of posttranslational modifications of th

Background: The adult medicinal leech central nervous system (CNS) is capable of regenerating specific synaptic circuitry after a mechanical lesion, displaying evidence of anatomical repair within a few days and functional recovery within a few weeks. In the present work, spatiotemporal changes in molecular distributions during this phenomenon are explored. Moreover, the hypothesis that neural regeneration involves some molecular factors initially employed during embryonic neural development is tested. Results: Imaging mass spectrometry coupled to peptidomic and lipidomic methodologies allowed

Some animals can regenerate large missing regions of their nervous system, requiring mechanisms to restore the pattern, numbers, and wiring of diverse neuron classes. Because injuries are unpredictable, regeneration must be accomplished from an unlimited number of starting points. Coordinated regeneration of neuron-glia architecture is thus a major challenge and remains poorly understood. In planarians, neurons and glia are regenerated from distinct progenitors. We found that planarians first regenerate neurons expressing a Delta-encoding gene, delta-2, at key positions in the central and peri

Members of the COE family of transcription factors are required for central nervous system (CNS) development. However, the function of COE in the post-embryonic CNS remains largely unknown. An excellent model for investigating gene function in the adult CNS is the freshwater planarian. This animal is capable of regenerating neurons from an adult pluripotent stem cell population and regaining normal function. We previously showed that planarian coe is expressed in differentiating and mature neurons and that its function is required for proper CNS regeneration. Here, we show that coe is essentia

The resilience of regeneration in vertebrates is not very well understood. Yet understanding if tissues can regenerate after repeated insults, and identifying limitations, is important for elucidating the underlying mechanisms of tissue plasticity. This is particularly challenging in tissues, such as the nervous system, which possess a large number of terminally differentiated cells and often exhibit limited regeneration in the first place. However, unlike mammals, which exhibit very limited regeneration of spinal cord tissues, many non-mammalian vertebrates, including lampreys, bony fishes, a

The cell neural adhesion molecule contactin-2 plays a key role in axon extension and guidance, fasciculation, and myelination during development. We thus asked, whether contactin-2 is also important in nervous system regeneration after trauma. In this study, we used an adult zebrafish spinal cord transection model to test the functions of contactin-2 in spinal cord regeneration. The expression patterns of contactin-2 at different time points after spinal cord injury were studied at the mRNA level by qPCR and in situ hybridization, and contactin-2 protein levels and immunohistological localizat

L1 is among the few adhesion molecules that favors repair after trauma in the adult central nervous system of vertebrates by promoting neuritogenesis and neuronal survival, among other beneficial features. In the peripheral nervous system, L1 is up-regulated in Schwann cells and regrowing axons after nerve damage, but the functional consequences of this expression remain unclear. Our previous study of L1-deficient mice in a femoral nerve injury model showed an unexpected improved functional recovery, attenuated motoneuronal cell death, and enhanced Schwann cell proliferation, being attributed

Some neurons, especially in mammalian peripheral nervous system or in lower vertebrate or in vertebrate central nervous system (CNS) regenerate after axotomy, while most mammalian CNS neurons fail to regenerate. There is an emerging consensus that neurons have different intrinsic regenerative capabilities, which theoretically could be manipulated therapeutically to improve regeneration. Population-based comparisons between “good regenerating” and “bad regenerating” neurons in the CNS and peripheral nervous system of most vertebrates yield results that are inconclusive or difficult to interpret. At least in part, this reflects the great diversity of cells in the mammalian CNS. Using mammalian nervous system imposes several methodical limitations. First, the small sizes and large numbers of neurons in the CNS make it very difficult to distinguish regenerating neurons from non-regenerating ones. Second, the lack of identifiable neurons makes it impossible to correlate biochemical changes in a neuron with axonal damage of the same neuron, and therefore, to dissect the molecular mechanisms of regeneration on the level of single neurons. This review will survey the reported responses to axon injury and the determinants of axon regeneration, emphasizing non-mammalian model organisms, which are often under-utilized, but in which the data are especially easy to interpret.

Neurons of the mammalian central nervous system fail to regenerate. Substantial progress has been made toward identifying the cellular and molecular mechanisms that underlie regenerative failure and how altering those pathways can promote cell survival and/or axon regeneration. Here, we summarize those findings while comparing the regenerative process in the central versus the peripheral nervous system. We also highlight studies that advance our understanding of the mechanisms underlying neural degeneration in response to injury, as many of these mechanisms represent primary targets for restoring functional neural circuits.

Background: It is well known that neurons of the peripheral nervous system do have the capacity to regenerate a severed axon leading to functional recovery, whereas neurons of the central nervous system do not regenerate successfully after injury. The underlying molecular programs initiated by axotomized peripheral and central nervous system neurons are not yet fully understood. Results: To gain insight into the molecular mechanisms underlying the process of regeneration in the nervous system, differential display polymerase chain reaction has been used to identify differntially expressed genes following axotomy of peripheral and central nerve fibers. For this purpose, axotomy induced changes of regenerating facial nucleus neurons and non-regenerating red nucleus and Clarke ‘s nucleus neurons have been analyzed in an intra-animal side-to-side comparison. One hundred and nine gene fragments have been isolated, of which 37 correspond to known genes encoding for a number of different functional classes of proteins such as transcription factors, signaling molecules, homeobox-genes, receptors and proteins involved in metabolism. Seventy-two gene-fragments did not show similarities to known genes. In this study differential display PCR was used as a screening method to analyze differntially expressed genes. Furthermore the method itself was established and critically assessed in terms of sensitivity and specificity.

Mammalian central nervous system (CNS) neurons have negligible posttraumatic regenerative capacity, whereas nerves of lower vertebrates and of the peripheral nervous system of mammals regenerate spontaneously after injury.

Spinal cord repair research appeared to have run out of new ideas in the 1970s. In a 1981 paper, the Aguayo Laboratory revisited an experiment by Tello and Cajal that suggested that central nervous system (CNS) axons could regenerate into peripheral nerve grafts. Using modern axon tracing methods, David and Aguayo showed that axons from neurons in the spinal cord could regenerate for long distances within peripheral nervous system (PNS) grafts, but not back into the CNS. This proved that damaged CNS tissue is inhibitory to axon regeneration while PNS tissue is permissive. The experiment sparked a research revival, leading to the identification of many inhibitory molecules that block axon growth in the mature CNS.

Abstract The ability of two electrical synapses (neuron L4‐R4 and neuron L19‐R19) to regenerate in the adult Helisoma nervous system was examined. The L4‐R4 electrical connection exhibited rapid restoration to 50% of normal strength, whereas L19‐R19 reconnection was weak or absent. This disparity is attributable to the inability of neuron 19 to sprout effectively across a crush site in the buccal commissure, although peripheral sprouting was pronounced. The factors which underlie the inability of neuron 19 (but not neuron 4) to sprout into a central environment are unknown, but dictate differential synapse restoration in this adult nervous system.

The ability of neurons in the brain of the goldfish to regenerate their axons was examined using anterograde and retrograde axonal tracing methods. It was found that all neurons in the thalamus and brainstem that project to the optic tectum can regenerate their axons after removal of the tectal lobe, and that their axons can often grow for considerably greater distances than they normally extend. In addition, they can penetrate (and, presumably, innervate) their normal target tissue, even if it is displaced into an ectopic location.

Some animals are able to regenerate all missing cell types and large body parts after bisection, a phenomenon often referred to as whole-body regeneration. The correct tissues and structures regenerate with remarkable fidelity according to the original polarity of the body, reflecting positional information present in the remaining tissue. Understanding the cellular and molecular basis of this positional information is a central question in regeneration biology. In planarians and acoels, muscle cells carry such positional information, but where this information originates and whether this function is conserved are not well understood. Here, we use the cnidarian Nematostella vectensis to address the role of the nervous system in whole-body regeneration. We generated a transgenic line for conditional ablation of neurons and showed that Nematostella can repeatedly regenerate its nervous system. Bisection experiments following nervous system ablation showed that all head fragments regenerate a second head instead of a foot, whereas foot fragments correctly regenerate the missing head. We further found that regenerating head fragments of nervous system-ablated animals increase the expression of Wnt signaling genes that in wild-type animals are only upregulated in regenerating foot fragments. These molecular changes and the initiation of ectopic head regeneration precede the reappearance of neurons, suggesting that the nervous system does not directly control whether a head or foot