Ndel1 Promotes Axon Regeneration via Intermediate Filaments (original) (raw)
Related papers
Axonal Organelles as Molecular Platforms for Axon Growth and Regeneration after Injury
International Journal of Molecular Sciences, 2021
Investigating the molecular mechanisms governing developmental axon growth has been a useful approach for identifying new strategies for boosting axon regeneration after injury, with the goal of treating debilitating conditions such as spinal cord injury and vision loss. The picture emerging is that various axonal organelles are important centers for organizing the molecular mechanisms and machinery required for growth cone development and axon extension, and these have recently been targeted to stimulate robust regeneration in the injured adult central nervous system (CNS). This review summarizes recent literature highlighting a central role for organelles such as recycling endosomes, the endoplasmic reticulum, mitochondria, lysosomes, autophagosomes and the proteasome in developmental axon growth, and describes how these organelles can be targeted to promote axon regeneration after injury to the adult CNS. This review also examines the connections between these organelles in developing and regenerating axons, and finally discusses the molecular mechanisms within the axon that are required for successful axon growth.
Axon Regrowth during Development and Regeneration Following Injury Share Molecular Mechanisms
Current Biology, 2012
Background: The molecular mechanisms that determine axonal growth potential are poorly understood. Intrinsic growth potential decreases with age, and thus one strategy to identify molecular pathways controlling intrinsic growth potential is by studying developing young neurons. The programmed and stereotypic remodeling of Drosophila mushroom body (MB) neurons during metamorphosis offers a unique opportunity to uncover such mechanisms. Despite emerging insights into MB g-neuron axon pruning, nothing is known about the ensuing axon re-extension. Results: Using mosaic loss of function, we found that the nuclear receptor UNF (Nr2e3) is cell autonomously required for the re-extension of MB g-axons following pruning, but not for the initial growth or guidance of any MB neuron type. We found that UNF promotes this process of developmental axon regrowth via the TOR pathway as well as a late axon guidance program via an unknown mechanism. We have thus uncovered a novel developmental program of axon regrowth that is cell autonomously regulated by the UNF nuclear receptor and the TOR pathway. Conclusions: Our results suggest that UNF activates neuronal re-extension during development. Taken together, we show that axon growth during developmental remodeling is mechanistically distinct from initial axon outgrowth. Due to the involvement of the TOR pathway in axon regeneration following injury, our results also suggests that developmental regrowth shares common molecular mechanisms with regeneration following injury. *Correspondence: oren.schuldiner@weizmann.ac.il Please cite this article in press as: Yaniv et al., Axon Regrowth during Development and Regeneration Following Injury Share Molecular Mechanisms, Current Biology (2012), http://dx.
A NUDEL-dependent mechanism of neurofilament assembly regulates the integrity of CNS neurons
Nature Cell Biology, 2004
The cytoskeleton controls the architecture and survival of central nervous system (CNS) neurons by maintaining the stability of axons and dendrites. Although neurofilaments (NFs) constitute the main cytoskeletal network in these structures, the mechanism that underlies subunit incorporation into filaments remains a mystery. Here we report that NUDEL, a mammalian homologue of the Aspergillus nidulans nuclear distribution molecule NudE, is important for NF assembly, transport and neuronal integrity. NUDEL facilitates the polymerization of NFs through a direct interaction with the NF light-subunit (NF-L). Knockdown of NUDEL by RNA interference (RNAi) in a neuroblastoma cell line, primary cortical neurons or post-natal mouse brain destabilizes NF-L and alters the homeostasis of NFs. This results in NF abnormalities and morphological changes reminiscent of neurodegeneration. Furthermore, variations in levels of NUDEL correlate with disease progression and NF defects in a mouse model of neurodegeneration. Thus, NUDEL contributes to the integrity of CNS neurons by regulating NF assembly.
Axonal Regeneration: Underlying Molecular Mechanisms and Potential Therapeutic Targets
Biomedicines
Axons in the peripheral nervous system have the ability to repair themselves after damage, whereas axons in the central nervous system are unable to do so. A common and important characteristic of damage to the spinal cord, brain, and peripheral nerves is the disruption of axonal regrowth. Interestingly, intrinsic growth factors play a significant role in the axonal regeneration of injured nerves. Various factors such as proteomic profile, microtubule stability, ribosomal location, and signalling pathways mark a line between the central and peripheral axons’ capacity for self-renewal. Unfortunately, glial scar development, myelin-associated inhibitor molecules, lack of neurotrophic factors, and inflammatory reactions are among the factors that restrict axonal regeneration. Molecular pathways such as cAMP, MAPK, JAK/STAT, ATF3/CREB, BMP/SMAD, AKT/mTORC1/p70S6K, PI3K/AKT, GSK-3β/CLASP, BDNF/Trk, Ras/ERK, integrin/FAK, RhoA/ROCK/LIMK, and POSTN/integrin are activated after nerve injury...
Extrinsic cellular and molecular mediators of peripheral axonal regeneration
Cell and Tissue Research, 2012
The ability of injured peripheral nerves to regenerate and reinnervate their original targets is a characteristic feature of the peripheral nervous system (PNS). On the other hand, neurons of the central nervous system (CNS), including retinal ganglion cell (RGC) axons, are incapable of spontaneous regeneration. In the adult PNS, axonal regeneration after injury depends on well-orchestrated cellular and molecular processes that comprise a highly reproducible series of degenerative reactions distal to the site of injury. During this finetuned process, named Wallerian degeneration, a remodeling of the distal nerve fragment prepares a permissive microenvironment that permits successful axonal regrowth originating from the proximal nerve fragment. Therefore, a multitude of adjusted intrinsic and extrinsic factors are important for surviving neurons, Schwann cells, macrophages and fibroblasts as well as endothelial cells in order to achieve successful regeneration. The aim of this review is to summarize relevant extrinsic cellular and molecular determinants of successful axonal regeneration in rodents that contribute to the regenerative microenvironment of the PNS.
Key molecules in axon regeneration
Biologija, 2013
Development of adult mammal central nervous system (CNS) is closely related to loosing the ability spontaneously regenerate after injuries. On the other hand, peripheral nervous system (PNS) maintains its capability to regenerate after injuries entire lifespan. Ability to regenerate successfully is mainly determined by the balance of growth promoting and growth inhibiting factors, expressed by both neuronal and non-neuronal cells found in the injury site. Some of signaling cues involved in regeneration are expressed in adult CNS constantly, although expression of other factors occurs only in the injury site of adult mammal. Ephrins, Semaphorins, Slits and Netrins are among most important molecules involved in lack of success in regeneration of CNS. PNS neurons initiate reparation mechanisms right after development of injury, and are capable to recover functional activity even if an area of injury is more than several centimeters wide. Understanding of differences between CNS and PNS regeneration and factors involved in functional nervous system recovery are crucial for both in depth analysis of plasticity of adult mammal neural system, and for developing new treatment strategies.
Developmental neurobiology, 2018
Injury to the brain and spinal cord has devastating consequences because adult central nervous system (CNS) axons fail to regenerate. Injury to the peripheral nervous system (PNS) has a better prognosis, because adult PNS neurons support robust axon regeneration over long distances. CNS axons have some regenerative capacity during development, but this is lost with maturity. Two reasons for the failure of CNS regeneration are extrinsic inhibitory molecules, and a weak intrinsic capacity for growth. Extrinsic inhibitory molecules have been well characterized, but less is known about the neuron-intrinsic mechanisms which prevent axon re-growth. Key signaling pathways and genetic/epigenetic factors have been identified which can enhance regenerative capacity, but the precise cellular mechanisms mediating their actions have not been characterized. Recent studies suggest that an important prerequisite for regeneration is an efficient supply of growth-promoting machinery to the axon; howe...
Achieving CNS axon regeneration by manipulating convergent neuro-immune signaling
Cell and Tissue Research, 2012
After central nervous system (CNS) trauma, axons have a low capacity for regeneration. Regeneration failure is associated with a muted regenerative response of the neuron itself, combined with a growth-inhibitory and cytotoxic postinjury environment. After spinal cord injury (SCI), resident and infiltrating immune cells (especially microglia/macrophages) contribute significantly to the growth-refractory milieu near the lesion. By targeting both the regenerative potential of the axon and the cytotoxic phenotype of microglia/macrophages, we may be able to improve CNS repair after SCI. In this review, we discuss molecules shown to impact CNS repair by affecting both immune cells and neurons. Specifically, we provide examples of pattern recognition receptors, integrins, cytokines/chemokines, nuclear receptors and galectins that could improve CNS repair. In many cases, signaling by these molecules is complex and may have contradictory effects on recovery depending on the cell types involved or the model studied. Despite this caveat, deciphering convergent signaling pathways on immune cells (which affect axon growth indirectly) and neurons (direct effects on axon growth) could improve repair and recovery after SCI. Future studies must continue to consider how regenerative therapies targeting neurons impact other cells in the pathological CNS. By identifying molecules that simultaneously improve axon regenerative capacity and drive the protective, growth-promoting phenotype of immune cells, we may discover SCI therapies that act synergistically to improve CNS repair and functional recovery.
Transcriptional insights on the regenerative mechanics of axotomized neurons in vitro
2012
One of the striking features of the injured central nervous system (CNS) is the failure of severed axons to adequately regenerate to restore loss of function. This was initially believed to be caused by an intrinsic inability of injured axons to sprout regenerative processes. However, the seminal studies of Albert Aguayo and others using peripheral or cellular tissue grafts transplanted into the lesioned spinal cord have clearly demonstrated that the environment of the injured CNS is a critical determinant of whether injured axons can regenerate . The molecular determinates of the inhibitory CNS environment are now well-understood, with major players being myelin-associated molecules (such as nogo, myelin-associated glycoprotein) and chondroitin sulphate proteoglycans .
Molecular and Cellular Neuroscience, 2021
Peripheral nerve trauma and regeneration are complex events, and little is known concerning how occurrences in the distal stump affect the cell body's response to injury. Intermediate filament (IF) proteins underpin cellular architecture and take part in nerve cell proliferation, differentiation and axon regeneration, but their role in these processes is not yet fully understood. The present study aimed to investigate the regulation and interrelationship of major neural IFs in adult dorsal root ganglion (DRG) neurons and satellite glial cells (SGCs) following sciatic nerve injury. We demonstrated that the expression of neural IFs in DRG neurons and SGCs after axotomy depends on vimentin activity. In intact DRGs, synemin M and peripherin proteins are detected in small neurons while neurofilament L (NFL) and synemin L characterize large neurons. Both neuronal populations are surrounded by vimentin positive-and glial fibrillary acidic protein (GFAP)-negative SGCs. In response to axotomy, synemin M and peripherin were upregulated in large wild-type DRG neurons and, to a lesser extent, in vim-/-and synm-/-DRG neurons, suggesting the role for these IFs in axon regeneration. However, an increase in the number of NFL-positive small neurons was observed in vim-/-mice, accompanied by a decrease of peripherin-positive small neurons. These findings suggest that vimentin is required for injury-induced neuronal IF remodeling. We further show that vimentin is also indispensable for nerve injury-induced GFAP upregulation in perineuronal SGCs and that inactivation of vimentin and synemin appears to accelerate the rate of DRG neurite regeneration at early stages in vitro.