The Questions of Developmental Biology

That it must be a sort of a surface reaction between each kind of nerve fiber and the particular structure to
be innervated seems clear from the fact that sensory and motor fibers, though running close together in the
same bundle, nevertheless form proper peripheral connections, the one with the epidermis and the other
with the muscle.. . .The foregoing facts suggest that there may be a certain analogy here with the union of
egg and sperm cell.
Research on the specificity of neuronal connections has focused on two major systems:
motor neurons, whose axons travel from the nerve to a specific muscle, and the optic system,
wherein axons originating in the retina find their way back into the brain. In both cases, the
specificity of axonal connections is seen to unfold in three steps (Goodman and Shatz 1993):
Pathway selection, wherein the axons travel along a route that leads them to a particular region
of the embryo.
Target selection, wherein the axons, once they reach the correct area, recognize and bind to a
set of cells with which they may form stable connections.
Address selection, wherein the initial patterns are refined such that each axon binds to a small
subset (sometimes only one) of its possible targets.
The first two processes are independent of neuronal activity. The third process involves
interactions between several active neurons and converts the overlapping projections into a finetuned
pattern of connections.
It has been known since the 1930s that motor axons can find their appropriate muscles
even if the neuronal activity of the axons is blocked. Twitty (who had been Harrison's student)
and his colleagues found that embryos of the newt Taricha torosa secreted a toxin, tetrodotoxin,
that blocked neural transmission in other species. By grafting pieces of T. torosa embryos onto
embryos of other salamander species, they were able to paralyze the host embryos for days while
development occurred. Normal neuronal connections were made, even though no neuronal
activity could occur. At about the time the tadpoles were ready to feed, the toxin wore off, and the
young salamanders swam and fed normally (Twitty and Johnson 1934; Twitty 1937). More recent
experiments using zebrafish mutants with nonfunctional neurotransmitter receptors similarly
demonstrated that motor neurons can establish their normal patterns of innervation in the absence
of neuronal activity (Westerfield et al. 1990).
But the question remains: How are the axons instructed where to go?
Cell adhesion and contact guidance: attractive and permissive molecules
The initial pathway a growth cone follows is determined by the environment the growth
cone experiences. The extracellular environment can provide substrates upon which to migrate,
and these substrates can provide navigational information to the growth cone. Some of the
substrates the growth cone encounters will permit it to adhere to them, and thus promote axon
migration. Other substrates will cause the growth cone to retract, and will not allow its axon to
grow in that direction. Some of the substrates can give extremely specific cues, recognized by
only a small set of neuronal growth cones, while other cues are recognized by large sets of
neurons. The migrational cues of the substrate can come from anatomical structures, the
extracellular matrix, or from adjacent cell surfaces.