The correct wiring of neuronal circuits depends on outgrowth and guidance of neuronal processes during development. In the past two decades, great progress has been made in understanding the molecular basis of axon outgrowth and guidance. Genetic analysis in Caenorhabditis elegans has played a key role in elucidating conserved pathways regulating axon guidance, including Netrin signaling, the slit Slit/Robo pathway, Wnt signaling, and others. Axon guidance factors were first identified by screens for mutations affecting animal behavior, and by direct visual screens for axon guidance defects. Genetic analysis of these pathways has revealed the complex and combinatorial nature of guidance cues, and has delineated how cues guide growth cones via receptor activity and cytoskeletal rearrangement. Several axon guidance pathways also affect directed migrations of non-neuronal cells in C. elegans, with implications for normal and pathological cell migrations in situations such as tumor metastasis. The small number of neurons and highly stereotyped axonal architecture of the C. elegans nervous system allow analysis of axon guidance at the level of single identified axons, and permit in vivo tests of prevailing models of axon guidance. C. elegans axons also have a robust capacity to undergo regenerative regrowth after precise laser injury (axotomy). Although such axon regrowth shares some similarities with developmental axon outgrowth, screens for regrowth mutants have revealed regeneration-specific pathways and factors that were not identified in developmental screens. Several areas remain poorly understood, including how major axon tracts are formed in the embryo, and the function of axon regeneration in the natural environment.

https://www.genetics.org/content/genetics/204/3/849.full.pdf

The Genetics of Axon Guidance and Axon Regeneration in Caenorhabditis elegans

Highly regulated cell migration events are crucial during animal tissue formation and the trafficking of cells to sites of infection and injury. Misregulation of cell movement underlies numerous human diseases, including cancer. Although originally studied primarily in two-dimensional in vitro assays, most cell migrations in vivo occur in complex three-dimensional tissue environments that are difficult to recapitulate in cell culture or ex vivo Further, it is now known that cells can mobilize a diverse repertoire of migration modes and subcellular structures to move through and around tissues. This review provides an overview of three distinct cellular movement events in Caenorhabditis elegans-cell invasion through basement membrane, leader cell migration during organ formation, and individual cell migration around tissues-which together illustrate powerful experimental models of diverse modes of movement in vivo We discuss new insights into migration that are emerging from these in vivo studies and important future directions toward understanding the remarkable and assorted ways that cells move in animals.

https://www.genetics.org/content/genetics/208/1/53.full.pdf

Invading, Leading and Navigating Cells in Caenorhabditis elegans: Insights into Cell Movement in Vivo.

Guided migrations of cells and developing axons along the dorso-ventral (D/V) and antero-posterior (A/P) body axes govern tissue patterning and neuronal connections. In C. elegans, as in vertebrates, D/V and A/P graded distributions of UNC-6/Netrin and Wnts, respectively, provide instructive polarity information to guide cells and axons migrating along these axes. By means of a comprehensive genetic analysis, we found that simultaneous loss of Wnt and Netrin signaling components reveals previously unknown and unexpected redundant roles for Wnt and Netrin signaling pathways in both D/V and A/P guidance of migrating cells and axons in C. elegans, as well as in processes essential for organ function and viability. Thus, in addition to providing polarity information for migration along the axis of their gradation, Wnts and Netrin are each able to guide migrations orthogonal to the axis of their gradation. Netrin signaling not only functions redundantly with some Wnts, but also counterbalances the effects of others to guide A/P migrations, while the involvement of Wnt signaling in D/V guidance identifies Wnt signaling as one of the long sought mechanisms that functions in parallel to Netrin signaling to promote D/V guidance of cells and axons. These findings provide new avenues for deciphering how A/P and D/V guidance signals are integrated within the cell to establish polarity in multiple biological processes, and implicate broader roles for Netrin and Wnt signaling - roles that are currently masked due to prevalent redundancy.

/pdf/netrins-and-wnts-function-redundantly-to-regulate-antero-xxv16ykyfa.pdf

Netrins and Wnts function redundantly to regulate antero-posterior and dorso-ventral guidance in C. elegans.

Synaptic Protein Degradation Controls Sexually Dimorphic Circuits through Regulation of DCC/UNC-40.

How extracellular molecules influence the direction of axon guidance is poorly understood. The HSN axon of Caenorhabditis elegans is guided towards a ventral source of secreted UNC-6 (netrin). The axon’s outgrowth response to UNC-6 is mediated by the UNC-40 (DCC) receptor. We have proposed that in response to the UNC-6 molecule the direction of UNC-40-mediated axon outgrowth is stochastically determined. The direction of guidance is controlled by asymmetric cues, including the gradient of UNC-6, that regulate the probability that UNC-40-mediated axon outgrowth is directed on average, over time, in a specific direction. Here we provide genetic evidence that a specialized extracellular matrix, which lies ventral to the HSN cell body, regulates the probability that UNC-40-mediated axon outgrowth will be directed ventrally towards the matrix. We show that mutations that disrupt the function of proteins associated with this matrix, UNC-52 (perlecan), UNC-112 (kindlin), VAB-19 (Kank), and UNC-97 (PINCH), decrease the probability of UNC-40-mediated axon outgrowth in the ventral direction, while increasing the probability of outgrowth in the anterior and posterior directions. Other results suggest that INA-1 (α integrin) and MIG-15 (NIK kinase) signaling mediate the response in HSN. Although the AVM axon also migrates through this matrix, the mutations have little effect on the direction of AVM axon outgrowth, indicating that responses to the matrix are cell-specific. Together, these results suggest that an extracellular matrix can regulate the direction of UNC-6 guidance by increasing the probability that UNC-40-mediated axon outgrowth activity will be oriented in a specific direction.

/pdf/extracellular-matrix-regulates-unc-6-netrin-axon-guidance-by-3isxln8s8r.pdf

Extracellular Matrix Regulates UNC-6 (Netrin) Axon Guidance by Controlling the Direction of Intracellular UNC-40 (DCC) Outgrowth Activity

How the direction of axon guidance is determined is not understood. In Caenorhabditis elegans the UNC-40 (DCC) receptor mediates a response to the UNC-6 (netrin) guidance cue that directs HSN axon development. UNC-40 becomes asymmetrically localized within the HSN neuron to the site of axon outgrowth. Here we provide experimental evidence that the direction of guidance can be explained by the stochastic fluctuations of UNC-40 asymmetric outgrowth activity. We find that the UNC-5 (UNC5) receptor and the cytoskeletal binding protein UNC-53 (NAV2) regulate the induction of UNC-40 localization by UNC-6. If UNC-40 localization is induced without UNC-6 by using an unc-53 mutation, the direction of UNC-40 localization undergoes random fluctuations. Random walk models describe the path made by a succession of randomly directed movement. This model was experimentally tested using mutations that affect Wnt/PCP signaling. These mutations inhibit UNC-40 localization in the anterior and posterior directions. As the axon forms in Wnt/PCP mutants, the direction of UNC-40 localization randomly fluctuates; it can localize in either the anterior, posterior, or ventral direction. Consistent with a biased random walk, over time the axon will develop ventrally in response to UNC-6, even though at a discrete time UNC-40 localization and outgrowth can be observed anterior or posterior. Also, axon formation is slower in the mutants than in wild-type animals. This is also consistent with a random walk since this model predicts that the mean square displacement (msd) will increase only linearly with time, whereas the msd increases quadratically with time for straight-line motion.

https://bio.biologists.org/content/biolopen/early/2013/10/18/bio.20136346.full.pdf

Experimental evidence for UNC-6 (netrin) axon guidance by stochastic fluctuations of intracellular UNC-40 (DCC) outgrowth activity

Complex Regional Pain Syndrome: Evidence-Based Advances in Concepts and Treatments.

OBJECTIVE
The objective was to qualitatively synthesize all reported cases of complications, adverse effects, side effects, or harms arising from the use of scrambler therapy (ST).


METHODS AND DESIGN
A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, assessing the PubMed, Embase, Scopus, Web of Science, United States National Library of Medicine clinical trials registry, and Cochrane Central Register of Controlled Trials databases, searching from database inception to December 10th, 2021. Case reports/series, abstracts, retrospective studies, and prospective studies (e.g., open-label trials, randomized controlled trials) pertaining to ST and any description of a complication, adverse effect, side effect, or harm were screened. The search protocol was developed a priori and registered via the International Prospective Register of Systematic Reviews (PROSPERO ID: CRD42021291838).


RESULTS
A total of six RCTs, 19 prospective open-label trials, and 11 case series/case reports met inclusion criteria, comprising 1152 total patients. Two patients experienced contact dermatitis, and one patient reported minor ecchymosis that resolved without intervention. This yielded a composite complication rate of 0.26% (3/1152). There were zero reported serious adverse events.


CONCLUSIONS
When used in accordance with the treatment protocols described by the United States Food and Drug Administration and device manual, ST is associated with a reported composite complication rate that is magnitudes of order lower than that of invasive neuromodulation devices. ST neuromodulation is a safe alternative for patients who cannot undergo invasive neuromodulation device implantation either due to risk or preference.

Safety of Scrambler Therapy: A Systematic Review of Complications and Adverse Effects.

Neurons extend processes that vary in number, length, and direction of outgrowth Extracellular cues help determine the patterning of outgrowth In Caenorhabditis elegans, neurons respond to the extracellular UNC-6 (netrin) cue via UNC-40 (DCC) and UNC-5 (UNC5) receptors We have postulated that UNC-40 undergoes stochastically orientated asymmetric localization (SOAL) within neurons Extracellular cues govern the probability of UNC-40 localizing and mediating outgrowth at points along the surface of the neuron For each instance of time there is a probability that UNC-40-mediated outgrowth will occur in a specific direction and so over time the direction of outgrowth fluctuates Random walk modeling predicts that the degree of fluctuation affects the extent of outgrowth movement Therefore, different patterns of outgrowth could be caused by regulating UNC-40 SOAL Here we present evidence that UNC-5 (UNC5) receptor activity regulates UNC-40 SOAL and affects the length and number of processes that neurons develop We find that loss of UNC-5 function increases the probability of UNC-40-mediated outgrowth in different directions, thereby increasing the degree of fluctuation Consistent with the model, in unc-5 loss-of-function mutants neurons fail to extend processes to full length or fail to develop multiple processes We further show genetic interactions that suggest the UNC-5 and SAX-3 (Robo) receptors, and the cytoplasmic proteins, UNC-53 (NAV2), MIG-15 (NIK kinase), and MADD-2 (TRIM), function through specific signaling pathways to regulate UNC-40 SOAL in response to the UNC-6 and EGL-20 (wnt) extracellular cues We propose genes influence the patterning of neuronal outgrowth by regulating the SOAL process

https://www.biorxiv.org/content/biorxiv/early/2017/03/03/083436.full.pdf

Stochastic Model of Neuronal Outgrowth Movement: UNC-5 (UNC5) Regulates the Length and Number of Neuronal Processes in Caenorhabditis elegans

Neurons extend processes that vary in number, length, and direction of outgrowth. Extracellular cues help determine outgrowth patterns. In Caenorhabditis elegans, neurons respond to the extracellular UNC-6 (netrin) cue via UNC-40 (DCC) and UNC-5 (UNC5) receptors. Previously we presented evidence that UNC-40 asymmetric localization at the plasma membrane is self-organizing and that UNC-40 can localize and mediate outgrowth at randomly selected sites. We also postulate that the process is statistically dependent, i.e. if the probability of outgrowth at one site changes then the probability at another site(s) must also change. Over time, the direction of outgrowth activity fluctuates across the membrane. A probability distribution describes the likelihood of outgrowth in each direction. Random walk modeling predicts that the degree to which the direction of outgrowth fluctuations affects the outward displacement of the membrane. We predict that extracellular cues create patterns of outgrowth by differentially affecting the degree to which the direction of outgrowth activity fluctuates along the membrane. This produces different rates of outgrowth along the surface and creates patterns of extension. Here we present evidence that UNC-5 (UNC5) receptor activity regulates UNC-40 asymmetric localization and the patterning of outgrowth. We show that unc-5 mutations alter UNC-40 asymmetric localization and the patterns of outgrowth that neurons develop. Genetic interactions suggest UNC-5 acts through the UNC-53 (NAV2) cytoplasmic protein to regulate UNC-40 asymmetric localization in response to both the UNC-6 and EGL-20 (wnt) extracellular cues.

https://www.biorxiv.org/content/biorxiv/early/2017/08/28/083436.full.pdf

UNC-5 (UNC5) mediates neuronal outgrowth patterning in Caenorhabditis elegans by regulating UNC-40 (DCC) asymmetric localization

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