In grasshopper embryo limb buds, the sibling Ti1 pioneers are the first neurons to initiate axonogenesis. The pioneer growth cones migrate from the limb tip to the CNS along a in direction comprising discrete steering events. Filopodial exploration of the cellular terrain in the vicinity of the advancing growth cone appears to be important for steering. Some information is available on the identity of cells and cell types, on cell-surface characteristics, and on the involvement of basal lamina in these steering decisions. In the work reported here, we have used computer-enhanced fluorescence video microscopy to examine filopodial behavior and the process of growth cone migration and reorientation resulting from interactions with the normal guidance cues on the in situ substrate. We observed several different kinds of migration and steering events, which appear to be related to the absolute and relative affinities of the contacted substrates. On a relatively homogeneous substrate of intrasegmental epithelium, growth cones advance by extending veils between filopodia, as is commonly observed on uniform substrates in vitro. Where growth cones confront an orthogonal border between substrates of dissimilar affinity, they remain on the higher-affinity substrate by extending new branches along it. Subsequently, reorientation in the preferred direction on the higher-affinity substrate is accomplished by regression of branches extended in the nonselected direction. By contrast, a single filopodial contact with a very high-affinity substrate, such as a guidepost neuron, can reorient a growth cone, even when it is migrating on a favorable substrate. In this situation, the filopodium that contacts the high-affinity substrate expands in diameter until it becomes the nascent axon.

https://www.jneurosci.org/content/jneuro/10/12/3935.full.pdf

Pioneer growth cone steering decisions mediated by single filopodial contacts in situ.

Nerve cell growth is influenced by guiding properties of its substratum. Microfabricated cell culture substrata were used to determine whether rat dorsal root ganglia (DRG) nerve cells could detect and integrate simultaneous model adhesive and topographic guidance cues. Interference reflection microscopy demonstrated strips of surface contact under the marginal zone of growth cones on planar surfaces which were coincident with actin immunostaining at the periphery of the C-domain. Clusters of focal contacts below the growth cone C-domain delineated the track edges on adhesive gratings. Neurite extension was guided most effectively by adhesive gratings of 25-µm period where highly aligned cells were typically bipolar. Nanometric steps and differences in surface texture between the adhesive tracks was detected using atomic force microscopy (AFM). Neurites did not align to 12-to l00-µm pitch grooves which were less than 1 µm deep. The proportion of aligned neurites increased with groove depth. Maximum neurite alignment was seen when 6-.im-deep, 25-11m-wide grooves contained superimposed parallel adhesive tracks of matched pitch. Neurites aligned preferentially to adhesive tracks superimposed orthogonally over shallow grooves (1 µm deep). Primary neurites aligned increasingly to grooves with orthogonal adhesive tracks as their depth increased. These neurites frequently had highly branched terminal arbours aligned to the orthogonal adhesive tracks. We conclude that morphogenetic guidance cues can interact synergistically and hierarchically to steer nerve cell growth.

Morphogenetic guidance cues can interact synergistically and hierarchically in steering nerve cell growth

Tropomyosin Localization Reveals Distinct Populations of Microfilaments in Neurites and Growth Cones

The structural mechanisms responsible for the gradual elaboration of the cytoplasmic elongation of neurons are reviewed. In addition to discussing recent work, important older work is included to inform newcomers to the field how the current perspective arose. The highly specialized axon and the less exaggerated dendrite both result from the advance of the motile growth cone. In the area of physiology, studies in the last decade have directly confirmed the classic model of the growth cone pulling forward and the axon elongating from this tension. Particularly in the case of the axon, cytoplasmic elongation is closely linked to the formation of an axial microtubule bundle from behind the advancing growth cone. Substantial progress has been made in understanding the expression of microtubule-associated proteins during neuronal differentiation to stiffen and stabilize axonal microtubules, providing specialized structural support. Studies of membrane organelle transport along the axonal microtubules produced an explosion of knowledge about ATPase molecules serving as motors driving material along microtubule rails. However, most aspects of the cytoplasmic mechanisms responsible for neurogenesis remain poorly understood. There is little agreement on mechanisms for the addition of new plasma membrane or the addition of new cytoskeletal filaments in the growing axon. Also poorly understood are the mechanisms that couple the promiscuous motility of the growth cone to the addition of cytoplasmic elements.

Cytoplasmic mechanisms of axonal and dendritic growth in neurons

We have examined the relationship between tension, an intrinsic stimulator of axonal elongation, and the culture substrate, an extrinsic regulator of axonal elongation. Chick sensory neurons were cultured on three substrata: (a) plain tissue culture plastic; (b) plastic treated with collagen type IV; and (c) plastic treated with laminin. Calibrated glass needles were used to increase the tension loads on growing neurites. We found that growth cones on all substrata failed to detach when subjected to two to threefold and in some cases 5-10-fold greater tensions than their self-imposed rest tension. We conclude that adhesion to the substrate does not limit the tension exerted by growth cones. These data argue against a "tug-of-war" model for substrate-mediated guidance of growth cones. Neurite elongation was experimentally induced by towing neurites with a force-calibrated glass needle. On all substrata, towed elongation rate was proportional to applied tension above a threshold tension. The proportionality between elongation rate and tension can be regarded as the growth sensitivity of the neurite to tension, i.e., its growth rate per unit tension. On this basis, towed growth on all substrata can be described by the simple linear equation: elongation rate = sensitivity x (applied tension - tension threshold) The numerical values of tension thresholds and neurite sensitivities varied widely among different neurites. On all substrata, thresholds varied from near zero to greater than 200 mudynes, with some tendency for thresholds to cluster between 100 and 150 mudynes. Similarly, the tension sensitivity of neurites varied between 0.5 and 5.0 microns/h/mudyne. The lack of significant differences among sensitivity or threshold values on the various substrata suggest to use that the substratum does not affect the internal "set points" of the neurite for its response to tension. The growth cone of chick sensory neurons is known to pull on its neurite. The simplest cytomechanical model would assume that both growth cone-mediated elongation and towed growth are identical as far as tension input and elongation rate are concerned. We used the equation above and mean values for thresholds and sensitivity from towing experiments to predict the mean growth cone-mediated elongation rate based on mean rest tensions. These predictions are consistent with the observed mean values.

https://rupress.org/jcb/article-pdf/118/3/655/1063225/655.pdf

A cytomechanical investigation of neurite growth on different culture surfaces.

To determine the relationship between growth cone structure and motility, we compared the neurite extension rate, the form of individual growth cones, and the organization of f-actin in embryonic (E21) and postnatal (P30) sympathetic neurons in culture. Neurites extended faster on laminin than on collagen, but the P30 nerites were less than half as long as E21 neurites on both substrata. Growth cone shape was classified into one of five categories, ranging from fully lamellipodial to blunt endings. The leading margins of lamellipodia advanced smoothly across the substratum ahead of any filopodial activity and contained meshworks of actin filaments with no linear f-actin bundles, indicating that filopodia need not underlie lamellipodia. Rapid translocation (averaging 0.9-1.4 microns/min) was correlated with the presence of lamellipodia; translocation associated with filopodia averaged only 0.3-0.5 microns/min. This relationship extended to growth cones on a branched neurite where the translocation of each growth cone was dependent on its shape. Growth cones with both filopodial and lamellipodial components moved at intermediate rates. The prevalence of lamellipodial growth cones depended on age of the neurites; early in culture, 70% of E21 growth cones were primarily lamellipodial compared to 38% of P30 growth cones. A high percentage of E21 lamellipodial growth cones were associated with rapid neurite elongation (1.2 mm/day), whereas a week later, only 16% were lamellipodial, and neurites extended at 0.5 mm/day. Age-related differences in neurite extension thus reflected the proportion of lamellipodial growth cones present rather than disparities in basic structure or in the rates at which growth cones of a given type moved at different ages. Filopodia and lamellipodia are each sufficient to advance the neurite margin; however, rapid extension of superior cervical ganglion neurites was supported by lamellipodia independent of filopodial activity.

Rapid growth cone translocation on laminin is supported by lamellipodial not filopodial structures

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Rapid growth cone translocation on laminin is supported by lamellipodial not filopodial structures