The Questions of Developmental Biology

The results of these in vitro studies have been corroborated by gene knockout
experiments, wherein the deletion of particular neurotrophic factors causes the loss of only
particular subsets of neurons (Crowley et al. 1994; Jones et al. 1994). Another neurotrophin, glial
cell line-derived neurotrophic factor (GDNF), enhances the survival of another group of neurons:
the midbrain dopaminergic neurons whose destruction characterizes Parkinson disease (Lin et al.
1993). This neurotrophic factor can prevent the death of these neurons in adult brains (see
Lindsay 1995).
The actual survival of any given neuron in the embryo may depend on a combination of
agents. Schmidt and Kater (1993) have shown that neurotrophic factors, depolarization
(activation), and interactions with the substrate all combine synergistically to determine neuronal
survival. For instance, the survival of chick ciliary ganglion neurons in culture was promoted by
FGF, laminin, or depolarization. However, FGF did not promote survival when laminin was
absent, and the combined effects of laminin, FGF, and depolarization were greater than the
summed effects of each of them (Figure 13.27). The neurotrophic factors and the other
environmental agents appear to function by
suppressing an apoptotic "suicide program"
that would be constitutively expressed
unless repressed by these factors (Raff et
al. 1993). The survival of retinal ganglion
cells in culture is dependent on
neurotrophic factors, but these cells can
respond to these factors only if they have
been depolarized (Meyer-Franke et al.
1995). Moreover, since neuronal activity
stimulates the production of neurotrophins
by the active nerves, it is likely that
neurons receiving a signal produce more neurotrophins (Thoenen 1995). These factors could have
an effect on nearby synapses that are active (i.e., capable of responding to the neurotrophins),
thereby stabilizing a set of active synapses to the exclusion of inactive ones.
The discovery and purification of neurotrophic proteins and the analysis of their
interactions with substrate and electrical conditions may make new therapies for
neurodegenerative diseases possible. Numerous pharmaceutical companies are starting clinical
trials of neurotrophic factors for the possible alleviation of spinal cord injuries (NGF), Parkinson
disease (GDNF), amyotrophic lateral sclerosis (BDNF, CNTF), peripheral neuropathies (NGF,
NT-3), and Alzheimer disease (NGF, GDNF).
Paths to glory: migration of the retinal ganglion axons
Nearly all the mechanisms for neural specification and selectivity mentioned in this
chapter can be seen in the ways in which individual retinal neurons send axons to the appropriate
areas of the brain. Even when retinal neurons are transplanted far away from the eye, they are
able to find these areas (Harris 1986). This ability to guide the axons of translocated neurons to
their appropriate target sites implies that the guidance cues are not distributed solely along the
normal pathway, but exist throughout the embryonic brain. Guiding an axon from a nerve cell
body to its destination across the embryo is a complex process, and several different types of cues
may be used simultaneously to ensure that the correct connections get established.