Pioneer axon is the classification given to axons that are the first to grow in a particular region. They originate from pioneer neurons, and have the main function of laying down the initial growing path that subsequent growing axons, dubbed follower axons, from other neurons will eventually follow.
Several theories relating to the structure and function of pioneer axons are currently being explored. The first theory is that pioneer axons are specialized structures, and that they play a crucial role in guiding follower axons. The second is that pioneer axons are no different from follower axons, and that they play no role in guiding follower axons.
Anatomically, there are no differences between pioneer and follower axons, although there are morphological differences. The mechanisms of pioneer axons and their role in axon guidance is currently being explored. In addition, many studies are being conducted in model organisms, such grasshoppers, zebrafish, and fruit flies to study the effects of manipulations of pioneer axons on neuronal development.
History
Santiago Ramon y Cajal, considered the father of modern neuroscience, was one of the first to physically observe growing axons. Moreover, he observed that axons grew in a structured, guided manner. He advocated that axons were guided by chemotactic cues. Indeed, later experiments showed that in both invertebrate and vertebrate models, axons grew along pre-determined routes to create a reproducible scaffold of nerves.
Ramon y Cajal's views faced some competition from those of Paul Alfred Weiss, his contemporary neuroscientist during the 1920s and 1930s. Weiss argued that functional specificity did not depend on specific axon connections, and that nonspecific mechanical cues participated in guiding axons. Subsequent investigations into chemotactics cues that started in the 1970s eventually proved that Ramon y Cajal's initial ideas were intuitive and ahead of his time.[1]
Mechanisms of growth
The mechanism of growth of pioneer neurons has been investigated in the central and peripheral nervous systems of invertebrate animals. Observations of axon growth during the early embryonic period have led to conclusions that axons are actively guided to specific locations. Within these animal models, several factors have been identified as playing a role in determining the direction of growth.
Guidepost cells are specialized early differentiating sensory cells. These cells are essential in providing navigational information to pioneer axons. Arrays of pioneer neurons create short segments of pioneer axons extending distal to proximal within an appendage. The resulting trajectories are due to pioneer axons growing from guidepost to guidepost cells. In addition, pioneer axons can act as guidepost cells to more distant pioneer neurons.[1] Studies that involved selective destruction of guidepost cells resulted in pioneer axons becoming unable to navigate normally to the CNS from the PNS. Instead, the pioneer axons assumed alternate configurations and followed different trajectories. In addition, without the guidepost cells, the pioneer axons did not find the stereotyped route that pioneer axons would normally navigate.[2]
It has been shown that glial cells also play a role in axon guidance in various ways. In particular, glial cells demonstrate an interaction with the growth cones of pioneer axons. The route of extending growth cones has been shown to be abundant in glial cells, which are in turn part of a cellular mesh including other intermediate neurons and filopodia. Glial cells also participate in the fasciculation and defasciculation of axons, which are essential in shaping the pathways that are eventually followed.[3] A proposed mechanism involves the creation of a scaffold made out of interface glia, which growth cones contact during the establishment of axon tracts. Ablation of the interface glia leads to a complete loss of longitudinal pioneer axon tracts. In addition, ablation of glia in later embryonic development also interfered with guidance of follower axons, showing that glial cells are necessary in maintaining scaffold needed for contacting growth cones.[4]
Chemotactic influences
A variety of chemotactic cues provide essential signaling directing the directional growth of pioneer axons. Chemotactic cues are unique in that they can be multifunctional and versatile. A single chemotactic cue can both act as an attractant or repellent to pioneer axons, and may work from either a distance or within the immediate vicinity. More specifically, the interactions between chemotactic cues and growth cones can offer a possible explanation for the diversity that is observed in their behavior. Guidance molecules are heavily involved in steering the directions of growth cones. For example, guidance molecules can initiate, extend, stabilize, or retract individual filopodia, as well as attract various adhesion molecules to impact their physical state.
Some of the various chemotactic cues that have been explored in the mechanisms of pioneer axons include netrin, ephrin, semaphorin, Slit-Robo, and Notch. Receptors for these molecules have also been studied. Netrins primarily function as attractions of pioneer axons towards the midline. They can act from a distance as much as a few millimeters, as well as act in short range. Netrins can also act as a repellant. Unique among chemoattractants is that the function of netrin has been conserved among a variety of species across 600 million years. Like netrin, ephrin can function as both an attractant and repellant. Ephrins primarily play a role in setting a gradient along the anterior-poster axis for the guidance of developing retinal axons. Semaphorins, which were first identified on specific axons in the grasshopper CNS, function primarily as short-range inhibitory cues that steer pioneer axons away from less ideal regions. Receptor complexes for semaphorins include neuropilins and plexins.[5]
The Slit-Robo cell signaling pathway plays an important role in guiding pioneer axons, especially pioneer longitudinal axons. These axons, which function to connect major parts of the CNS, are mainly present during embryonic development. The Slit family mainly functions as a repellent towards longitudinal axons, guiding them away from the ventral midline. The loss of Slit in Drosophila caused the presence of longitudinal axons in the midline. In conjunction with the Robo receptor, Slit signaling played a role in determining tract positions parallel to the midline for longitudinal axons to follow during development. The loss of either Slit or Robo caused dysfunction in the development of longitudinal pioneer neurons in the midbrain and hindbrain of Drosophila.[6] Furthermore, it has been shown that Robo plays a diversified role in pioneer axon guidance in different areas of the brain during embryonic development. Primarily, Robo 1 is crucial towards pioneer longitudinal axon guidance in the ventral tract, while Robo 2 is important in the dorsal tract.[7]
The signaling associated with the receptor Notch, as well as non-canonical Notch/Abl signaling, have been shown to play a role in the development of longitudinal pioneer neurons in the Drosophilaventral nerve cord. The Notch receptor has been shown to interact with interface glia to form a path that longitudinal pioneer neurons can follow. Notch/Abl signaling in the pioneer neurons increases the motility of the growth cones of longitudinal pioneer axons while stimulating filopodia development. It has also been noted that Notch signaling is also important in the migration of neurons in the mammalian cortex.[8]
Anatomy
The directed growth of axons depends on structure at the end of the tip of a growing axon referred to as a growth cone. Growth cones, in brief, are motile structures that explore the environment and ultimately guide the extension of the axon. The response of growth cones to various signaling molecules dictates the correct pathway and direction of growth of the axon. Growth cones possess a sheetlike expansion at the tip called the lamellipodium, from which extend fine processes called filopodia. The growth cone is necessary for the construction of neural pathways.
Although pioneer axons and follower axons both possess growth cones, there are several morphological differences related to the function of pioneer axons. The structure of the growth cone changes whenever an axon reaches a territory not previously innervated, or if a choice in direction is required. Mainly, the lamellipodium increase in size and extend numerous filopodia in order to collect as much sensory information as possible.[9]
Role in neuronal development
The role of pioneer axons in neuronal development has been studied extensively in various invertebrate and vertebrate systems in both the central nervous system and peripheral nervous system. Although these experiments have shed light on the functions of the pioneer axons, the results reveal conflicting information into the extent of the effect of pioneer axons on proper development. In addition, other studies have shown that certain cells that interact with pioneer axons are also crucial in the eventual development of neural pathways, and that loss of these cells results in improper navigation of pioneer axons. Furthermore, identical pathways and homologous neurons across different species reflect different pathfinding abilities of growth cones in pioneer neurons.
Axonal pathfinding and fasciculation behaviour in the embryonic ventral nerve cord of Drosophila.
An investigation was conducted looking into the role of pioneer axons in the formation of both CNS and PNS axon pathways in a Drosophila embryo. Using a method to ablate specific neurons, the ablation of the aCC axon, which plays a role in pioneering the intersegmental nerve in the Drosophila PNS, resulted in the three typical follower axons becoming delayed and prone to pathfinding errors. Despite these consequences, eventually the pathway was formed in the majority of subjects. Ablation of the pioneer axons that formed the longitudinal tracts in the Drosophila CNS resulted in similar difficulties in the formation and organization of longitudinal pathways in 70% of observed segments. Ultimately, like in the PNS, the longitudinal pathways formed in about 80% of observed segments. Thus, it was shown that the pioneer axons played a role in the development of the CNS and PNS, and without the pioneer axons, the growth of the followers was delayed. Remarkably, the majority of the tracts formed, indicating that other factors play a role in axon guidance that can correct for the loss of pioneer neurons.[10]
Although studies of the mechanisms of pioneer axons have mostly been in invertebrate models, studies have also begun exploring the role of pioneer axons in the development of large vertebrate axon tracts. The primary model for these experiments has been in the zebrafish. Like in Drosophila, there is evidence to show that although pioneer axons play an important role in guiding the growth cones of follower axons, they may not be completely essential. The brain of the early zebrafish presents an ideal environment in which to study the behavior of developing axon tracts. The earliest differentiating pioneer neurons create a scaffold, with which growth cones of follower axons interact with.
Deletion of pioneer axons which create the scaffold have an effect on the growth cones of the neurons of the nucleus of the posterior commissure, in that they cannot follow the normal path of extending ventrally, then posteriorly. Despite the compromised pioneer neuron scaffold, the follower growth cones extend ventrally normally. However, around half of the followers do not follow the posterior longitudinal path correctly, while the other half do. This suggests that other cues other than those from pioneer axons play a role in guiding follower axon growth, and that pioneer axons may play different roles in different parts of neuronal development.[11] In a different study, replacement or removal of the early-born retinal ganglion cells, which function as pioneer neurons, had a significantly deleterious effect on the ability of later axons to exit the eye. Subsequent axon-axon interactions were also shown to be necessary, as misrouting of retinal axons led to chiasm defasciculaiton, telencephalic and ventral hindbrain projections, or aberrant crossing in the posterior commissure.[12]
An axon or nerve fiber is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action potentials away from the nerve cell body. The function of the axon is to transmit information to different neurons, muscles, and glands. In certain sensory neurons, such as those for touch and warmth, the axons are called afferent nerve fibers and the electrical impulse travels along these from the periphery to the cell body and from the cell body to the spinal cord along another branch of the same axon. Axon dysfunction can be the cause of many inherited and acquired neurological disorders that affect both the peripheral and central neurons. Nerve fibers are classed into three types – group A nerve fibers, group B nerve fibers, and group C nerve fibers. Groups A and B are myelinated, and group C are unmyelinated. These groups include both sensory fibers and motor fibers. Another classification groups only the sensory fibers as Type I, Type II, Type III, and Type IV.
A retinal ganglion cell (RGC) is a type of neuron located near the inner surface of the retina of the eye. It receives visual information from photoreceptors via two intermediate neuron types: bipolar cells and retina amacrine cells. Retina amacrine cells, particularly narrow field cells, are important for creating functional subunits within the ganglion cell layer and making it so that ganglion cells can observe a small dot moving a small distance. Retinal ganglion cells collectively transmit image-forming and non-image forming visual information from the retina in the form of action potential to several regions in the thalamus, hypothalamus, and mesencephalon, or midbrain.
Synaptogenesis is the formation of synapses between neurons in the nervous system. Although it occurs throughout a healthy person's lifespan, an explosion of synapse formation occurs during early brain development, known as exuberant synaptogenesis. Synaptogenesis is particularly important during an individual's critical period, during which there is a certain degree of synaptic pruning due to competition for neural growth factors by neurons and synapses. Processes that are not used, or inhibited during their critical period will fail to develop normally later on in life.
Axon guidance is a subfield of neural development concerning the process by which neurons send out axons to reach their correct targets. Axons often follow very precise paths in the nervous system, and how they manage to find their way so accurately is an area of ongoing research.
Netrins are a class of proteins involved in axon guidance. They are named after the Sanskrit word "netr", which means "one who guides". Netrins are genetically conserved across nematode worms, fruit flies, frogs, mice, and humans. Structurally, netrin resembles the extracellular matrix protein laminin.
A growth cone is a large actin-supported extension of a developing or regenerating neurite seeking its synaptic target. It is the growth cone that drives axon growth. Their existence was originally proposed by Spanish histologist Santiago Ramón y Cajal based upon stationary images he observed under the microscope. He first described the growth cone based on fixed cells as "a concentration of protoplasm of conical form, endowed with amoeboid movements". Growth cones are situated on the tips of neurites, either dendrites or axons, of the nerve cell. The sensory, motor, integrative, and adaptive functions of growing axons and dendrites are all contained within this specialized structure.
The floor plate is a structure integral to the developing nervous system of vertebrate organisms. Located on the ventral midline of the embryonic neural tube, the floor plate is a specialized glial structure that spans the anteroposterior axis from the midbrain to the tail regions. It has been shown that the floor plate is conserved among vertebrates, such as zebrafish and mice, with homologous structures in invertebrates such as the fruit fly Drosophila and the nematode C. elegans. Functionally, the structure serves as an organizer to ventralize tissues in the embryo as well as to guide neuronal positioning and differentiation along the dorsoventral axis of the neural tube.
Slit homolog 2 protein is a protein that in humans is encoded by the SLIT2 gene.
Netrin-1 is a protein that in humans is encoded by the NTN1 gene.
Slit homolog 1 protein is a protein that in humans is encoded by the SLIT1 gene.
The Roundabout (Robo) family of proteins are single-pass transmembrane receptors that are highly conserved across many branches of the animal kingdom, from C. elegans to humans. They were first discovered in Drosophila, through a mutant screen for genes involved in axon guidance. The Drosophila roundabout mutant was named after its phenotype, which resembled the circular traffic junctions. The Robo receptors are most well known for their role in the development of the nervous system, where they have been shown to respond to secreted Slit ligands. One well-studied example is the requirement for Slit-Robo signaling in regulation of axonal midline crossing. Slit-Robo signaling is also critical for many neurodevelopmental processes including formation of the olfactory tract, the optic nerve, and motor axon fasciculation. In addition, Slit-Robo signaling contributes to cell migration and the development of other tissues such as the lung, kidney, liver, muscle and breast. Mutations in Robo genes have been linked to multiple neurodevelopmental disorders in humans.
Slit is a family of secreted extracellular matrix proteins which play an important signalling role in the neural development of most bilaterians. While lower animal species, including insects and nematode worms, possess a single Slit gene, humans, mice and other vertebrates possess three Slit homologs: Slit1, Slit2 and Slit3. Human Slits have been shown to be involved in certain pathological conditions, such as cancer and inflammation.
Guidepost cells are cells which assist in the subcellular organization of both neural axon growth and migration. They act as intermediate targets for long and complex axonal growths by creating short and easy pathways, leading axon growth cones towards their target area.
Slit-Robo is the name of a cell signaling protein complex with many diverse functions including axon guidance and angiogenesis.
The growth cone is a highly dynamic structure of the developing neuron, changing directionality in response to different secreted and contact-dependent guidance cues; it navigates through the developing nervous system in search of its target. The migration of the growth cone is mediated through the interaction of numerous trophic and tropic factors; netrins, slits, ephrins and semaphorins are four well-studied tropic cues (Fig.1). The growth cone is capable of modifying its sensitivity to these guidance molecules as it migrates to its target; this sensitivity regulation is an important theme seen throughout development.
Fasciclin 2 is a 95 kilodalton cell membrane glycoprotein in the immunoglobulin (Ig) – related superfamily of cell adhesion molecules (CAMs). It was first identified in the developing grasshopper embryo, seen dynamically expressed on a subset of fasciculating axons in the central nervous system (CNS), functioning as a neuronal recognition molecule in the regulation of selective axon fasciculation. Subsequently, fasII was cloned and has mainly been studied in the fruit fly. Its extracellular structure consists of two Fibronectin type III domains and five Ig-like C2 domains, having structural homology to the neural cell adhesion molecule (NCAM) found in vertebrates. Alternative splicing of fasII gives rise to its expression in three major isoforms, including a membrane-associated form that is attached to the outer leaflet of the plasma membrane via a glycophosphatidylinositol linkage and two integral transmembrane forms. The larger transmembrane form has an amino acid motif contained in its cytoplasmic domain that is rich in proline, glutamic acid, serine and threonine residues. The fasciclin 1 (Fas1) and fasciclin 3 (Fas3) genes in Drosophila also code for cell adhesion proteins in the nervous system but do not show any structural or functional similarities with NCAM.
UNC is a set of proteins first identified through a set of screening tests in Caenorhabditis elegans, looking for roundworms with movement problems. Worms with which were un-coordinated were analysed in order to identify the genetic defect. Such proteins include UNC-5, a receptor for UNC-6 which is one of the netrins. Netrins are a class of proteins involved in axon guidance. UNC-5 uses repulsion (genetics) to direct axons while the other netrin receptor UNC-40 attracts axons to the source of netrin production.
UNC-5 is a receptor for netrins including UNC-6. Netrins are a class of proteins involved in axon guidance. UNC-5 uses repulsion to direct axons while the other netrin receptor UNC-40 attracts axons to the source of netrin production.
A follower neuron is a nerve cell that arises in the developmental stage of the brain and which growth and orientation is intrinsically related to pioneer neurons. These neurons can also be called later development neurons or follower cells. In the early stages of brain development, pioneer neurons define axonal trajectories that are later used as scaffolds by follower neurons, which project their growth cones and fasciculate with pioneer axons, forming a fiber tract and demonstrating a preference for axon-guided growth. It is thought that these neurons can read very accurate cues of direction and fasciculate or defasciculate in order to reach their target, even in a highly dense axon bundle.
Target selection is the process by which axons selectively target other cells for synapse formation. Synapses are structures which enable electrical or chemical signals to pass between nerves. While the mechanisms governing target specificity remain incompletely understood, it has been shown in many organisms that a combination of genetic and activity-based mechanisms govern initial target selection and refinement. The process of target selection has multiple steps that include Axon pathfinding when neurons extend processes to specific regions, cellular target selection when neurons choose appropriate partners in a target region from a multitude of potential partners, and subcellular target selection where axons often target particular regions of a partner neuron.
References
1 2 Raper, J., & Mason, C. (2010). Cellular Strategies of Axonal Pathfinding. [Article]. Cold Spring Harbor Perspectives in Biology, 2(9). doi: a00193310.1101/cshperspect.a001933
↑ Bentley, D., & Caudy, M. (1983). Pioneer axons lose directed growth after selective killing of guidepost cells. Nature, 304(5921), 62–65.
↑ Hidalgo, A., & Booth, G. E. (2000). Glia dictate pioneer axon trajectories in the Drosophila embryonic CNS. [Article]. Development, 127(2), 393–402.
↑ Hidalgo, A., Urban, J., & Brand, A. H. (1995). Targeted ablation of glia disrupts axon tract formation in the Drosophila CNS. Development, 121(11), 3703–3712.
↑ Dickson, B. J. (2002). Molecular mechanisms of axon guidance. Science, 298(5600), 1959–1964. doi: 10.1126/science.1072165
↑ Mastick, G. S., Farmer, W. T., Altick, A. L., Nural, H. F., Dugan, J. P., Kidd, T., & Charron, F. (2010). Longitudinal axons are guided by Slit/Robo signals from the floor plate. Cell Adh Migr, 4(3), 337–341.
↑ Kim, M., Roesener, A. P., Mendonca, P. R., & Mastick, G. S. (2011). Robo1 and Robo2 have distinct roles in pioneer longitudinal axon guidance. Dev Biol, 358(1), 181–188. doi: 10.1016/j.ydbio.2011.07.025
↑ Kuzina, I., Song, J. K., & Giniger, E. (2011). How Notch establishes longitudinal axon connections between successive segments of the Drosophila CNS. Development, 138(9), 1839–1849. doi: 10.1242/dev.062471
↑ Purves, D., Augustine, G. J., Fitzpatrick, D., Hall, W. C., LaMantia, A.-S., McNamara, J. O., & White, L. E. (2008). Neuroscience (4 ed.). Sunderland: Sinauer Associates Inc.
↑ Lin, D. M., Auld, V. J., & Goodman, C. S. (1995). Targeted neuronal cell ablation in the Drosophila embryo: pathfinding by follower growth cones in the absence of pioneers. Neuron, 14(4), 707–715.
↑ Patel, C. K., Rodriguez, L. C., & Kuwada, J. Y. (1994). Axonal outgrowth within the abnormal scaffold of brain tracts in a zebrafish mutant. J Neurobiol, 25(4), 345–360. doi: 10.1002/neu.480250402
↑ Pittman, A. J., Law, M. Y., & Chien, C. B. (2008). Pathfinding in a large vertebrate axon tract: isotypic interactions guide retinotectal axons at multiple choice points. Development, 135(17), 2865–2871. doi: 10.1242/dev.025049
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