Biology Reference
In-Depth Information
CO
MPETITION, DEATH AND THE TROPHIC THEO
RY
Chapter 22 emphasized that, although proliferation is a default behaviour for unicells, the
cells of multicellular organisms will proliferate only when they receive specific signals that
permit them to do so. The difference is in fact even more extreme: in animals, at least, the
default fate of cells seems to be to elect to die,
)
and they will survive only if provided
with specific signals.
40
This view of the control of cell populations is known as the 'trophic
theory'.
The trophic theory was first developed to explain remarkable properties of adaptive self-
organization that are displayed by the vertebrate nervous system. The limbs of tetrapods
receive their motor and sensory innervation from the ventral and dorsal roots, respectively,
of the spinal cord at axial levels corresponding to those of the limb. There are dorsal and
ventral roots between each vertebra along the animal's back, but those that have to serve
the limb as well as the trunk are significantly larger, and contain more cells, than those
that serve only the trunk. The size of pools of motor and sensory neurons that serve the limbs
cannot be set by an intrinsic property of the spinal cord itself because if a limb bud is removed
from a developing embryo, the pool of neurons on that side of the body shrinks to a size char-
acteristic of pools that do not serve limbs at all.
41
Observation of the spinal cord during development reveals that all axial levels show an
initial overproduction of neurons compared to the numbers that will be required in the adult
animal. The excess cells are removed by elective cell death, which takes place to a greater
extent where there is no limb than where a limb exists. For example, in developing chicks
40
e
50 percent of cells are lost even at the levels of developing limbs, and this loss exceeds
85 percent when the limbs are absent.
42,43
Observations such as this suggest that the limb
itself, the target of the axons of these neurons, may be the source of signals that promote their
survival. Experiments in which alternations in the precise size of limb muscles to be inner-
vated by the motor pool cause a corresponding alteration in the percentage of motor neurons
that survive, with a correlation coefficient better than 99 percent, support this hypothesis.
44
A long series of experiments (which have been reviewed elsewhere
22,45,46
) has demonstrated
that targets for innervation, such as muscles of the developing limb, are sources of limited
amounts of neurotrophic factors that promote the survival of neurons. Direct application
of neurotrophins such as NGF to the chick spinal cord greatly reduces the amount of elective
cell death that takes place there.
47
Many neurotrophins signal to cells via the Trk family of receptor tyrosine kinases (other
neurotrophic molecules, such as those in the GDNF family, use different receptor tyrosine
kinases). The details of how the signalling systems that are triggered by these extracellular
molecules inhibit mechanisms of elective cell death are complex and vary with cell type;
they are not completely understood but more details can be found from a number of excellent
reviews.
48
e
51
What is important from the point of view of regulation of neuronal number is
that the amount of survival factors produced by the neuronal targets is very small, and only
just enough to support the correct number of innervating neurons. Some time after
)
As they were in the chapter on proliferation, the cells of embryos too young to have shown any differ-
entiation may be exceptions to this rule, as zygotes obviously have to be.
