Healthcare and Medicine Reference
In-Depth Information
CHAPTER
4
Determination and Differentiation
The nervous system is a coral reef of the body where
evolution and development have collaborated to
produce an extraordinary diversity of cell types.
Neurons show enormous variety in cellular anatomy,
physiological function, neurochemistry, and connec-
tivity. For example, granule cells of the cerebellum are
tiny, and have simple dendrites and bifurcated axons
that release the excitatory transmitter glutamate,
whereas cerebellar Purkinje cells are huge, have an
impressively complex and electrically active dendritic
tree, a single long spiking axon, and release the
inhibitory neurotransmitter GABA. The differences
between neurons can be much more subtle. All the
motor neurons of the spinal cord share a common
morphology, chemistry, physiology, and circuitry, yet
they are distinctly specified molecularly so that they
connect with particular presynaptic partners and post-
synaptic muscles.
The fates of some neurons, particularly those of
invertebrates, are the products of particular lineages.
The fates of others, particularly those in vertebrates,
appear to depend more on the local environment.
Sydney Brenner suggested that neurons are either
European or American. A neuron is European if its fate
is largely the result of who its parents were. For Amer-
ican neurons, it is more about the neighborhood where
they grew up. When one looks closely, however, it
turns out that fate is not strictly controlled by either
lineage or environment alone. Usually, it is the mixture
of the two that is essential; the adoption of a particu-
lar fate is a multistep sequential process that involves
both intrinsic and extrinsic influences. A progenitor
cell may be externally influenced to take a step along
a particular fate pathway, and so the unborn daughter
of that cell has also, in a sense, taken the same step. A
signal from the environment may act upon this daugh-
ter cell to refine its fate further, and the response of the
daughter cell to the signal is to express an intrinsic
factor consistent with its limited fates.
The environment in which neural progenitors
divide and give rise to neurons is rich with diffusible
molecules, cell surface proteins, and extracellular
matrix factors. These extrinsic signals influence the
genes that developing neurons express, which direct
neuronal shape, axonal pathways, connectivity, and
chemistry. The number of genes used to carry out this
task of specification throughout the nervous system is
impressive. It has been estimated that half of an organ-
ism's genes are expressed exclusively in the nervous
system. Most of these are involved in various aspects
of neuronal differentiation.
Some of the basic techniques that are used in
approaching these questions are shown in Figure 4.1.
Transplantation is a good technique for finding out
whether a cell's fate has been intrinsically specified.
For example, a progenitor from a donor animal is
transplanted to a different part of a host animal. If the
fate of the cell is unaltered by putting it in this new
environment, then the cell is “autonomously deter-
mined” at the time of transplantation. If, however, the
cell adopts a new fate, consistent with the position to
which it was transplanted, then the fate at the time of
transplantation is still flexible and can be “determined
nonautonomously.” Putting cells into tissue culture is
another valuable technique. By isolating a cell from
the embryo entirely, it is possible to assay the state of
determination of a cell in the absence of all interac-
tions. An advantage of this experimental system is that
the culture medium and substrate can be controlled. In
this way, potential extrinsic cues can be added and
assayed for their effect on fate choice.
Avery informative approach for studying the
processes that lead neurons down particular differentia-
tion pathways, at least in terms of identifying the factors
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