Video transcript In this video, I want to talk about Schwann cells. Schwann cells are glia of the peripheral nervous system derived from neural crest cells and named after a person who described them. Schwann cells come in a couple of shapes. Some are fairly shapeless cells that have little troughs on their surface.
And the axons of neurons that have small diameter axons often just sit inside these troughs. So these are neurons with a soma. And I'm leaving off the dendrites. And these have small axons, small diameter axons.
And they'll just kind of sit in these little troughs on the surface of these Schwann cells. And these are called nonmyelinating Schwann cells. Several studies determined that the number of PSCs gradually increase after birth [ 54 ]. PSCs tend to be positioned at the presynaptic side, on top of the motor axon terminal, without the intervention of a basal lamina [ 55 , 56 ].
Recently a new population of fibroblast-like cells named kranocytes—NMJ-capping cells—was detected on the other side, above the basal lamina of the PSC, covering all other cells of the NMJ. They are thought to have important roles in the NMJ repair after nerve injury [ 59 , 60 ]. Kranocytes appear to communicate with PSCs via neuregulin signaling pathway to act synergistically after nerve damage [ 59 ]. Most studies about PSCs were performed either on amphibian frog or rodent mouse samples [ 53 ].
These active areas correspond on the opposite side to the folds of the sarcolemma, the postsynaptic element of the NMJ, which are rich in nicotinic acetylcholine receptors [ 52 , 61 ]. Although these cells do not take part in the initial formation of the axon-muscle junction, PSCs have key contributions in the next stages of NMJ development.
In animal models lacking SCs, the axon reaches the muscle in the initial step of the NMJ formation, but only for a brief time [ 62 , 63 ]. Soon after the contact between the axon and the muscle, PSCs intensively divide, sprout, and are primarily involved in the growth of the synapse [ 64 ]. PSCs are also involved in the physiological processes of polyneuronal innervation and synapse elimination.
PSCs are involved in the multiple innervation process of the muscles and suffer a regression in parallel with the axonal withdrawal [ 1 , 65 , 66 ]. After the process of axonal withdrawal, PSCs are engaged in the removal of nerve debris, through phagocytosis [ 67 ]. The signaling pathway which facilitates the survival and growth of PSCs and the tight communication between PSCs and motor axons is the neuregulin1-ErbB pathway [ 1 ].
PSCs have important roles in the maintenance of the NMJ during the adult life as the structural support. Ablation in PSCs on the adult NMJ does not impede the immediate structure and function of the synapse, but after a period of time, the motor axon terminals retract, and the NMJ collapses [ 64 , 68 ]. Thus PSCs have a significant contribution to the structural maintenance of the synapse under the action of physical factors such as the intense tractions between the nerve and the muscle [ 53 ].
These cells dynamically participate in the process of synaptic transmission of information between the motor axons and the muscles, having an important role in the modulation of NMJ activity [ 53 , 57 , 69 ]. When the nerve terminal increases its firing rate and a large amount of neurotransmitter is released in the synaptic cleft, a simultaneous increase of intracellular calcium occurs in PSCs [ 70 , 71 ].
A similar effect is obtained by applying exogenous acetylcholine and ATP, molecules normally released by the synaptic vesicles, to PSCs [ 51 ]. Moreover, the levels of intracellular calcium vary depending on the type of the nerve firing rate, either burst or continuous [ 72 ]. These events do not occur in the myelinating SCs and emphasize the detection of synaptic activity by PSCs and the modification of their cellular behavior secondary to the synaptic transmission [ 69 ].
This is similar to a decoding process of the synaptic activity. This transient raising modulates the synapse by intensifying the neuromuscular transmission. PSCs are expressed on the surface of several G protein-coupled receptors with contributions in the modulation of the synapse activity [ 73 ]. Evidences suggest that different ligands of these G protein-coupled receptors determine different changes in the neuromuscular transmission, as follows: a GTP analogue decreased the neurotransmitter release, while a GDP analogue reduced the synaptic depression [ 73 ].
These evidences confirm that the NMJ is a tripartite synapse. First of all, after nerve degeneration, PSCs develop phagocytic traits for the clearance of the debris from the nerve terminals [ 75 ]. Second of all, PSCs are involved in the guiding of reinnervation. A few days after the nerve injury, PSCs from the altered NMJ begin to abundantly sprout, and these new processes reach adjacent undamaged synapses [ 76 ].
The role of the newly formed bridges is to facilitate the nerve pathway to find the altered NMJ and to regenerate the synapse more rapidly [ 69 , 76 ]. However, satellite NMSCs seem to play a role in nerve regeneration after insult as well and might be involved in pathogenic pathways of neuropathic pain [ 77 ].
Studies on mouse models revealed that PSCs represent an important target of the autoimmune process, the cellular destruction is complement dependent, and this pathogenic mechanism might be relevant for the human disease [ 68 , 78 ].
Amyotrophic lateral sclerosis ALS is a challenge for both the clinician and the researcher due to the obscure pathological mechanisms that are still not completely understood. The role of glial cells in the pathophysiology of the disease is not clear yet. Most probably the SC modifications are a consequence of the neurodegeneration process. However in human patients with ALS, PSCs have abnormal features with cellular processes that extend into the synaptic cleft [ 79 ].
In an ultrastructural study on SMA mouse models, PSCs in the diaphragmatic muscle show changes in their morphology such as vacuole-like translucent profiles and an electron-dense cytoplasm [ 81 ].
Another study on SMA mouse models revealed that in the evolution of the disease, there is a progressive loss of PSCs, leading to an improperly remodeling and regeneration of the NMJ [ 82 ]. Recent studies showed that RSCs play a very important role in the development of peripheral nerves and regeneration after injury. RSCs are also involved in the modulation of pain sensitivity in peripheral sensory neuropathies.
Even in the absence of injury, disturbance in axonal-RSC interaction is followed by neuropathic pain. The Schwann cells undergo many changes during axonal regeneration. They active myelin breakdown and up-regulate the expression of cytokines a large group of proteins secreted by the immune system.
This up-regulation helps to recruit macrophages, which are specialised cells that function to detect and destroy harmful organisms. The macrophages are sent to the site of the injury to clean up the damage. The Schwann cells increase the amount of growth factors, such as neurotrophins, which are proteins that increase the survival and function of neurons.
They also secrete proteins such as laminin and collagen and cell adhesion molecules involved in binding with other cells to support the regeneration process. The stump of a damaged axon can sprout, allowing them to grow.
The Schwann cells arrange a regeneration pathway along a tube of the basal lamina. The sprout of the damaged axon can then grow through this tube which helps to stimulate and guide its regeneration. Due to this, the regenerated axons can reconnect with muscles and organs that they previously controlled with the help of the Schwann cells.
Schwann cells are therefore especially important as regenerated axons will not reach their target areas without their support. Schwann cell dysfunction is primarily associated with demyelinating diseases of the PNS. Demyelination in the PNS describes a pathologic process of destruction of myelin-supporting cells, therefore destroying normal myelin.
These dysfunctions could be as a result of genetic mutations, autoimmune responses, infections, and trauma. These causes can impair the myelination process and the functions of the Schwann cells and axons, eventually leading to neurodegeneration. The insulating myelin segments could be lost or destroyed, and conduction of neuronal electrical impulses down the axon can be diminished or blocked. Demyelinating diseases can range from acute to chronic and some symptoms of these diseases can be characterised as weakened reflexes, weakness, sensory loss, slower nerve conduction, and paralysis.
Disorders which cause damage to the myelin sheath of the PNS, ultimately affecting the function of Schwann cells and axons, are called peripheral demyelinating diseases. With this disorder, the immune system attacks healthy nerve cells in the PNS, resulting in symptoms of weakness, numbness, and may eventually cause paralysis, making it a life-threatening condition if this disease affects the muscles involved with respiration.
Guillain-Barre Syndrome causes damage to the axons of neurons, leading to a blockage of electrical conduction. Although this condition damages the axons, the Schwann cells are also damage as a result, producing something called secondary demyelination.
Guillain-Barre Syndrome can be treated through intravenous immunoglobulin which is a treatment comprised of blood donation that contain healthy antibodies, in order to prevent harmful antibodies damaging the axons of neurons. Charcot-Marie-Tooth disease CMT is another peripheral demyelinating disorder that is rare and hereditary.
One interesting hypothesis is that the distinction between the ability of SCs vs. OLs to facilitate repair after injury is rooted in fundamental qualities that distinguish these cells, such as the number of axons they associate with and myelinate. It is intriguing to speculate that OLs may link circuits through their interactions with and myelination of multiple axons. However, in the PNS, where circuits are less complex, there is not strong evidence for SC participation in active modulation of circuit function.
Rather, more emphasis seems to be placed on the ability of SCs to rapidly and faithfully respond to injuries, which occur more readily in the PNS. Presumably, this rapid response would be more difficult if SCs were required to demyelinate more than one axon, especially if only some of those axons were injured, while others were intact. Fbxw7 mutants represent a unique and useful tool with which to investigate the impact of differences between myelinating SCs, Remak SCs, and OLs on nervous system repair.
Moreover, our work demonstrates a previously unknown plasticity of SCs and suggests that the demarcation between the cell biology of SC and OL myelination may be less rigid than previously appreciated. Requests for further information, resources, and reagents should be directed to and will be fulfilled by Kelly Monk monk ohsu.
In all cases, mice of both sexes were analyzed, in equal ratios whenever possible. In all cases mutants were compared with littermate sibling controls. All mouse lines were genotyped as previously described 10 , 11 , Samples were then washed with 0. Nerves were then dehydrated with increasing concentrations of ethanol followed by propylene oxide PO. Eleven different regions of interest were imaged and analyzed across two technical experiments.
The movie shown is a representative example. The experimenter was blind to the genotypes of the mice during all data acquisition. We then calculated the total distance traveled and the horizontal activity beam breaks over the entire chamber.
We used the pole test to evaluate performance of a complex motor task that requires skilled forelimb use, strength, and balance In addition, the time required for the mouse to climb down to the base of the pole was recorded. Cold sensitivity of the hind paws was measured by applying a drop of acetone to the plantar surface of the hind paw.
Five separate applications of acetone were applied to each hind paw. For each application the mouse was observed for 5 min. The percentage of applications for which the mouse responded shaking, licking, or elevating the hind paw to acetone application was recorded for each mouse We used the Noldus CatWalk XT system to quantify multiple locomotor and gait parameters including: run speed, stride length, paw print area mm 2 , maximum contact area mm 2 , and maximum contact mean intensity arbitrary units [a.
Briefly, the mouse voluntarily traverses a meter-long glass plate and its footprints are captured by a video camera. CatWalk XT quantifies parameters related to print dimensions and gait dynamics.
The innocuous mechanical thresholds of both hind paws were assessed with the von Frey test. Mice were placed in plastic behavior boxes with open bottoms on a wire mesh.
Varying diameter von Frey monofilaments Stoelting, Chicago, IL were pressed against the plantar surface of the hind paw until the filament bent.
The force applied to the hind paw is dependent on the diameter of the filament. We performed three trials on each paw. The withdrawal latencies obtained in each of the six trials were averaged to obtain the withdrawal latency for each mouse. Briefly, DRGs were isolated from individual embryonic day DRGs were washed with L15 medium and then incubated in 0. Data represent two technical replicate cultures from each of three independent mouse embryos per genotype.
To assess mTOR protein levels in the sciatic nerve, we dissected nerves from the sciatic notch to just proximal to the trifurcation.
Western blot images were quantified using FIJI. During this incubation time, and while still in TRIzol, nerves were cut into much smaller pieces using microdissection scissors. Samples were homogenized via disruption with a plastic-tipped electric homogenizer, followed by passage through a syringe and Once the nerves had been homogenized, we proceeded as usual with the standard TRIzol RNA extraction procedure as per manufacturer instructions. All controls including housekeeping genes, positive controls for amplification, and controls for genomic DNA contamination were included as standards in the array.
Genomic contamination was negligible in all samples. This list is not intended to represent an exhaustive list of Fbxw7 targets. Using Excel, we searched the raw data for the gene names of Fbxw7 , mTOR , and our candidate targets. Fluorescent images were obtained with a Zeiss AxioImager microscope. All data were quantified blindly. Statistically significant differences were determined using one-way ANOVA for all experiments with more than two groups but only one dependent variable.
Figure legends specify which test was used for specific experiments. In all cases, asterisks immediately above a bar indicate the significance of that sample relative to the control sample. If not indicated otherwise, the comparison was not significant. Further information on research design is available in the Nature Research Reporting Summary linked to this article.
No new genomic datasets were generated or analyzed during the current study. Nave, K. Myelination and support of axonal integrity by glia. Nature , — Arroyo, E. On the molecular architecture of myelinated fibers. Cell Biol. Simons, M. Wrapping it up: the cell biology of myelination. Czopka, T. Individual oligodendrocytes have only a few hours in which to generate new myelin sheaths in vivo.
Cell 25 , — Axon-glial signaling and the glial support of axon function. Snyder, J. Fbxw7 regulates Notch to control specification of neural precursors for oligodendrocyte fate. Neural Dev. Kearns, C. Fbxw7 limits myelination by inhibiting mTOR signaling. Sanchez, N.
Whole genome sequencing-based mapping and candidate identification of mutations from fixed zebrafish tissue. G3 7 , — Davis, R. Tumor suppression by the Fbw7 ubiquitin ligase: mechanisms and opportunities. Cancer Cell 26 , — Jaegle, M. Genes Dev. Thompson, B. Control of hematopoietic stem cell quiescence by the E3 ubiquitin ligase Fbw7. Taveggia, C. Neuregulin-1 type III determines the ensheathment fate of axons.
0コメント