A cure for spinal paralysis is not currently within reach, but with continuing research into neural regeneration, the future is promising. In order to regain functioning of the spinal cord, and thus motor control of the affected parts of the body, neurons of the spinal cord must grow and make new connections in the damaged area. The complexity of neural connections, demonstrated by this array of axons synapsing at a single neuron, is highly determined by the processes of embryonic development, and recreating this after damage is a daunting endeavor. The ability of axons to regenerate and reestablish connections is dependent on the properties of the neuron itself and the environment it is in. Unlike many rapidly regenerating cell types in the body, such as skin cells or liver cells, neural cells very rarely replace themselves after very early development. In mammals, new neurons are produced in the adult brain in only two regions—the granule cell layer of the olfactory bulb, and the dentate gyrus of the hippocampus. In order to work toward eventual control of regeneration in the central nervous system, normal neural development must be understood. Three key components of neural development are neuron differentiation, axon growth, and synapse formation.
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Potential neurons undergo a series of decisions in the process of differentiation—they must differentiate into neurons, and then into particular neural subtypes, and then find appropriate axonal targets. In order to promote regeneration into a particular region, each of these decisions must be understood and manipulated.
In embryonic development, neurons emerge from the neural tube, which is the precursor to the brain and the spinal cord. The neural tube is established on the back (dorsal) side of the developing embryo because of the differential concentration of molecules called morphogens. Neural fates are established by blocking the morphogen BMP and by promoting a biochemical pathway called Notch-Delta. Depending upon their location within the neural tube and the time of their differentiation, some cells will become neurons.
Their location and time of emergence from the spinal cord also determines which type of neuron they will become. In normal development, neurons emerging from the belly side (ventral side) of the neural tube become motor neurons controlling muscle movement, whereas neurons emerging from the dorsal side become sensory neurons relaying information from the periphery to the central nervous system. Still other cells will become interneurons that remain within the spinal cord and modify signals going both into and out of the central nervous system. In the specification of motor neurons, for example, their location near in the ventral side of the neural tube means they are exposed to certain chemicals including a protein called Sonic hedgehog (SHH) that is produced by a group of cells under the neural tube. In fact, these neurons require two separate surges of SHH in order to differentiate into motor neurons. At different concentrations, morphogens like SHH turn on certain genes that are specific to each cell type.
After cell-type differentiation, the axons must grow to specific targets either in the periphery or within the spinal cord and brain. Again, the concentrations of proteins made during embryonic development are necessary for the axon to know where to grow. The direction of axon growth within a region of the body is determined by the time when the neuron emerges from the spinal cord. Axon targets are established by morphogens before the axons even leave the spinal cord.
Axon growth is accomplished by extension of the end of the axon, called the growth cone. Pushed by internal lamellapodia and fillapodia, the edges of the growth cone move outward and sample the surrounding environment in order to choose the direction of growth.
In figure (A), nerve growth factor promotes axons to grow out in all directions. When nerve growth factor is paired with a chemorepellent semaphorin (placed to the right of the growing neurons), the axons grow away from it.
Once axons emerge from the spinal cord, their growth is determined both by the type of axon they have become and by the types of molecules and cells they encounter. Receptors on the surface of the axon growth cone detect signals that either promote or inhibit their growth in certain directions. Axons need specific signals both to grow toward their targets and also to stay alive once they reach their destination. Very early in neuroscience, it was discovered that axons grow along paths of pioneer axons and of glial support cells. Axons must choose a path to a target region, and then choose the specific cell or cells that they will innervate.
Substances that the axons can migrate along will promote axon growth. Sometimes these surfaces will have very specific signaling molecules that will promote the growth of only very specific types of axons. Other signals will be inhibitory and cause the growth cone to pull away and grow in a different direction. The signals can be freely diffusing in the fluid surrounding the cells or attached to nearby cells. Once axons reach their destination, the must also stop growing. This cessation of growth is also triggered by signals from the surrounding tissue.
Once axons reach their targets, they must preferentially form connections with particular cells. There is some flexibility in the cell types that each neuron will connect with, however, neurons will not establish connections with just any cell. Each neuron will have surface signals that will interact with their targets in a preference hierarchy. They will adhere most strongly to their preferred target, but can form synapses with other less preferred targets. This flexibility will be useful in the reinnervation of target cells by whatever neurons are available after injury, but it can also lead to inappropriate connection formation.