Perhaps the most remarkable feature of the nervous system is
the accuracy of its synaptic connections. The networks of circuits formed by
neuronal interactions are responsible for the generation of behavior. Synapse
formation is finely regulated. It involves processes at the cellular and subcellular
levels, which result in: axons finding their appropriate targets from an array
of choices; synapses being formed on the correct cellular compartment; and formation
of pre- and postsynaptic specializations that allow for efficient information
transfer.
We will discuss the following topics:
Axon Pathfinding – how axons find their
way to specific targets.
guidance forces – forces that are produced by guidance
molecules.
guidance molecules – proteins that help with axonal guidance.
Target recognition – how do axons "know" they have found the correct
target?
One general property of neurons is that they migrate from the sites at which they
begin to differentiate to their final residence in the nervous system.
Some neurons migrate to these final positions before they extend processes
(e.g., motor neurons).
Other neurons extend axons as they migrate (e.g., cerebellar granule neurons).
Granule cells in the developing cerebellum migrate long distances along the processes
of radial glial cells; this migration begins in the external granule layer and
ends at the granule cell layer. For example, epithelial cells at the luminal surface
of the neural tube proliferate to give rise to neuroblasts; some neuroblasts become
radial glial cells and extend their processes from the luminal to pial surface.
During the development of the cerebellum, granule neurons migrate through the
molecular layer along the processes of radial glial cells. A number of neurological
mutants have provided invaluable information about neuronal migration. For example,
in the "weaver" mutant mouse the genetic defect is in granule neurons and not
radial glia. In weaver, the granule cells are not able to migrate to their normal
position below the Purkinje cell layer. This defect results in abnormal synaptic
circuitry and impaired motor behavior.
Figure 9.1
Once neurons have migrated to their final position, and
sometimes before, they begin to extend axons. Neurons extend axons because
of a specialized structure at the end of axons called growth cones. Granule
cells in the developing cerebellum migrate long distances along the processes
of radial glial cells. This migration begins in the external granule layer
and ends at the granule cell layer.
Axon Pathfinding
Figure 9.2
A developing neuron extends multiple dendrites and a
single axon.
Neurons differentiate from multipotent stem cells and migrate to their
final residence in the nervous system. When these neurons reach their residence,
they extend an axon and dendrites to send and receive (respectively) information
from other neurons. In general, dendrites remain relatively close to the
cell body of the neuron, whereas axons may travel long distances to enable
interneuronal communication.
Since axons may
travel long distances and must search out their target from among many possibilities,
the growing end of the axon, or growth
cone, must have a mechanism to sense its surroundings.
Figure 9.3
A single axon grows from a cell with a
growth cone at its tip (center box) and eventually forms a synapse with
a target cell. Click on the left box to see an
enlarged image corresponding to axonal outgrowth, The center box to
see an axon being influenced by its environment during pathfinding,
and the right box for axon-target interactions resulting in synapse
formation.
Figure 9.4
Anatomy of a growth cone.
The distal tip of a growing axon is called the growth
cone. Actin is highly concentrated in both the lamellipodia
and the finger-like extensions (filopodia).
Although the direction of growth cone movement is influenced by the extracellular
environment, the growth cone itself possesses intrinsic mechanisms that
enable forward movement. Actin is polymerized at the leading edge of the
growth cone and moved towards the rear where is it depolymerized. This continuous
cycling movement of polymerized actin away from the leading edge towards
the rear and the movement of actin monomer to the leading edge again generates
a "tank-tread" type of movement. If this actin-based movement is linked
to the substrate on which the growth cone is moving, the "tank-tread" movement
is endowed with traction and growth cone movement ensues.
Ramón y Cajal first described growth cones and observed that they move in a
circuitous route towards their targets. This observation suggested that the
growth cones play an active role in the pathfinding process. Roger Sperry later
showed that after lesions of the optic nerve in the frog, retinotectal axons
regenerate, find their targets, and make synaptic connections with precision.
Based on these observations, Sperry suggested the existence of surface markers
that are used by the growth cones for pathway and target recognition. Later
studies in grasshopper embryo, Drosophila, chick, and zebrafish showed
that growth cones follow specific pathways in a variety of species. Since axon
pathfinding is similar in disparate species, the mechanisms underlying axon
guidance are likely conserved. Understanding the cellular and molecular mechanisms
that determine the guidance of growing axons is important because it underlies
the initial wiring of the nervous system, but also because it is necessary if
there is to be regeneration of function after injury.
