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.
In
this section:
- Neuron
Differentiation
- Axonal
Growth
- Synapse
Formation
- Trophic
Factors
- Peripheral
Nervous System Repair
- Transplants
in the Spinal Cord
NEURON DIFFERENTIATION
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.
(top)
AXONAL GROWTH
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.
(top)
SYNAPSE FORMATION
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.
(top)