91av

The growing embryo gradually acquires the tissues and organs that will enable
it to live independently. Understanding how the nervous system develops to
meet the demands of the growing body may help to solve the problem of
repairing it when it is injured

THE NERVOUS system – the brain and spinal cord, and the nerves that connect
these to the muscles and organs – is the control centre of our body, allowing
us to interact with the outside world and to keep in touch with the needs of
the world enclosed by our skin. It carries information from our senses, which
the brain interprets in the light of past experience; the brain then responds
by generating commands which pass through the nerves to the appropriate parts
of the body.

The whole system is immensely complex, involving thousands of millions of
nerve cells, or neurons. Each of these neurons may be linked with up to a
thousand other cells at connections or synapses, where they communicate with
each other by releasing chemicals called neurotransmitters.

For an animal to find food, a footballer to score a goal or a scientist to
explore the physics of the Universe, these neurons need to be organised in
precisely connected networks.

Even a touch on the hand, for example, involves a signal being passed along
sensory neurons in the arm, into the spinal cord and up to the brain, with the
signal passing, like a relay baton, from the synapse on one neuron to another
at least three times. It arrives in a region of the brain that deals only with
touch, which interprets the signal and communicates with neurons in the area
of the brain concerned with movement. This will respond to the touch by
sending out appropriate signals, perhaps to withdraw the hand, via the motor
neurons.

How are such networks built up? Does the set of instructions contained in the
genetic material of each nerve cell direct the connection of every last
synapse? Or does the position of each neuron and the synapses it forms depend
on other influences at work in the developing embryo?

Of course genes are important. However, it would be impossible for the genetic
code, powerful as it is, to carry all the information involved in the huge
task of wiring the body. We now know that, at each stage of development,
neurons receive signals from their environment which tell them where to go and
what to do.

By the time we are born, our full complement of nerve cells is already in
place. We will never acquire any more, and those that are lost, through
disease, injury or age, will not be replaced. This does not mean that the
system is complete at birth. There is still a lot to do to refine the
connections between neurons. These connections will continue to be modified,
possibly throughout our lives.

This modifiability, or plasticity, is essential if we are to form new memories
and learn new skills. But it is limited to the fine detail of the connections,
and the flexibility gradually declines as we grow older. If the brain is
damaged after birth there is little or no scope for rewiring to compensate for
the damage. One aim of studying the initial development of the nervous system
in the embryo is to discover what sets these limits to the growth of mature
neurons.

From egg to embryo

The first nerve cells

WHEN a sperm fertilises an egg cell, the egg divides first into two, then into
four and so on until a new individual forms. To begin with, the embryo is a
simple ball of apparently identical cells. At this stage, in mammals, each
cell has the potential to give rise to any of the many tissues and organs that
make up our body. A key question for those studying embryonic development is
at which level of subdivision a cell becomes committed to a single option.

The first sign of certain cells being earmarked for a future in the nervous
system occurs at about 10-14 days in the human embryo. A dimple appears in the
surface, which gradually deepens, as if someone were pressing a finger into a
soft rubber ball. At this point, the infolded layer of cells, known as the
mesoderm, lies under part of the outer or ectodermal layer. Chemical signals
pass from the mesoderm to the ectodermal cells, instructing the latter to
begin the construction of the brain and spinal cord. From now on, these
ectodermal cells are irreversibly committed to being nervous system cells, as
well as to the region along the body’s axis they will occupy.

They start by forming a structure known as the neural plate, a sheet of about
125 000 cells. This rapidly undergoes dramatic changes: it elongates and forms
a groove down the centre, whose sides roll up to form a tube. The neural tube
closes first in the area that will become the neck, and then progressively
upwards and downwards. It becomes detached from the overlying ectoderm, and
develops into the spinal cord – the main thoroughfare for communication
between the brain and the rest of the body. Meanwhile, three swellings appear
at the head end, which are the primitive subdivisions of the brain. In human
beings, all this has taken place by the end of the fourth week after
conception.

Scientists still do not fully understand how the primitive shapes of body and
organs develop from a simple ball of cells. Genes obviously decide whether the
embryo will turn out to be a frog or a rat or a human being, although at this
stage the embryos all look remarkably similar. But just as the formation of
the neural plate depends on contact between the mesoderm and the ectoderm, it
seems that local interactions encourage cells to congregate so as to form
these rudimentary shapes.

A recent advance is the discovery of cell adhesion molecules (CAMs)
distributed on the surfaces of cells. These control the stickiness of one cell
to another, or of cells to the substrates – surfaces – on which they are
growing. There are a number of different CAMs, each of which may stick
exclusively to one substrate, so restricting the pathways open to the cells
that bear them. One, the neuronal cell adhesion molecule, is concentrated in
the nervous system. The number of these molecules increases and diminishes at
different times during the early development, increasing or decreasing a
cell’s chances of changing its position.

Differentiation

Who does what

ONCE the neural tube has closed along its entire length, its cells begin to
reproduce themselves rapidly. They divide on the inner surface of the tube,
and the daughter cells migrate outwards. Following migration, the cells stop
dividing and differentiate – that is, they take on the specialised identities
that will fit them for the roles they have to perform.

The mature nervous system contains many different types of nerve cell. Some
are large, some are small; some are long and spindly, others round and densely
branching: according to type, they use one or more of the few dozen
neurotransmitters so far indentified. A cell’s size, shape and chemical
characteristics all help to define its role. What, then, influences a newly
formed cell to become one particular type of neuron?

A variety of experiments, such as those of the French embryologist Nicole Le
Douarin, have led to the conclusion that the environment in which an
undifferentiated cell finds itself is a critical influence. For example, a
cell may detect a chemical whose concentration increases from one end of the
embryo to the other. Once in position, a cell may also change its properties
in response to patterns of electrical activity or chemicals secreted by its
neighbours.

These and other interactions with the environment may determine the neuron’s
final identity through switching on or off the genes for producing transmitter
chemicals, cell adhesion molecules or proteins for building new membrane.
Exactly how they do this is largely unknown. The result, though, is usually
permanent: the scope for change in a fully differentiated nervous system is
very small.

Getting there

Movement of nerve cells

ALL CELLS in the body face the task of getting themselves to approximately the
right place to carry out their functions. A neuron, though, must take up the
right position with respect to its neighbours and also send out a long fibre,
or axon, to make contact with appropriate target cells. Both tasks require
feats of navigation that scientists are only beginning to understand.

Newly generated cells move outwards from the inner surface of the neural tube
to its outer layers. For some of these cells, a scaffolding is already in
place to guide them to their destinations.

The radial glial cells put out long thin fibres that stretch from the inside
to the outside of the neural tube, in a pattern as orderly as the spokes of a
wheel. Once the business of constructing the brain is complete, these glial
cells disappear or change their function. Migrating nerve cells that are
destined to become part of the cerebral cortex, the outer part of the brain
responsible for conscious experience, simply follow the radial glial fibres.

Once in place, a cell has to make contact with others. Most types of nerve
cell grow a mass of branching dendrites to receive incoming signals from other
cells. Different types of cell grow dendritic “trees” of characteristic
shapes, but the precise arrangement of the dendrites depends on a cell’s
inputs.

The neurons also grow one (or less frequently two) axons to transmit signals.
In the embryo, the axons, which are only a few micrometres across, may have to
navigate distances of several centimetres – for example, those that connect
the spinal cord with muscles in the toes.

The growing axons have specialised structures at their tips, called growth
cones. These can extend and retract threadlike extensions as well as broader
sheets of cytoplasm, and are packed with the cellular machinery for making new
tissue. The axons extend by adding this material just behind the growth cone.
So, how do these axons know where to go, and what tells them to stop when they
arrive?

We do not know the full explanation, but almost certainly they are in constant
touch with their surroundings, looking for signposts to help them on their
way. Growing axons seem, literally, to feel or sniff their way along.

An idea that has been very influential is that of chemospecificity. The Nobel
prizewinner Roger Sperry proposed that each cell had its own chemical
identity, as well as the chemical “address” of its ultimate destination. The
idea is still being tested. Recent laboratory experiments suggest that the
concept should be broadened to include a wide range of processes that may be
at work to guide growing axons.

When immature nerve cells are grown in glass dishes in the laboratory, a
number of factors influence their direction, which could also be at work in
the living body.

They tend to send their axons along scratches in the glass dish, suggesting
that they look for preformed pathways or lines of least resistance. They
prefer to grow on adhesive surfaces, and there are various proteins in the
body that might provide differentially sticky routes through the tissues,
acting in conjunction with the adhesion molecules on the cell’s surface. They
are attracted or repelled by electric fields of different polarity; such
fields exist naturally in the developing embryo. Lastly, they turn towards
nearby sources of body chemicals such as nerve growth factor (see below).

Overall, it seems likely that all these operate at different times and places;
for example, differential stickiness may be important in getting an axon into
the vicinity of its destination, while local chemicals may be more important
in helping it to home in on the right target.

Cell death

Only the fittest survive

BETWEEN 30 and 75 per cent of all cells generated in the nervous system die by
the time the system is complete. This seems rather wasteful, but it makes good
sense in an organ of such complexity as the brain.

Cell death in development is a way of matching the number of neurons to the
needs of the developing brain. Removing one limb from a chick in the egg
before the axons of motor neurons arrive leads to many more cells dying than
normal. On the other hand, grafting on an extra limb bud means that a larger
number survive.

It seems that the cells compete for limited supplies of a growth factor
provided by the target. Like wild birds competing for scarce food in winter,
those who lose out will die. Scientists assume that there are many specific
growth factors (a term that encompasses any chemical that a cell needs to grow
or survive) but have identified only a handful so far. The best known is a
protein called nerve growth factor, or NGF.

The sensory neurons that bring information from the skin and organs to the
spinal cord cannot survive without NGF. In addition, they will not grow axons
if kept in isolation without either pure NGF or some of their target tissues.
Rita Levi-Montalcini, an Italian cell biologist, discovered in the 1950s that
a cluster of such cells isolated in a glass dish and provided with NGF quickly
produced a dense halo of fibres.

As well as regulating the number of surviving cells, competition ensures that
axons that have grown in the wrong direction will be among those weeded out,
because they will fail to reach a source of the particular growth factor they
need. Some physiologists think that competition between cells is important in
the early development of the nervous system. Such a concept is helpful, for
example, in explaining how neurons become synaptically linked into circuits
and networks as memories and skills are learned. In this case, rather than
whole cells being eliminated, it is probably a question of competition between
individual synapses.

After birth

Time for fine tuning

EXACTLY how neurons recognise and make contact with their opposite numbers at
synapses is almost entirely unknown for most parts of the nervous system, but
some form of chemical recognition is almost certainly involved. The precision
with which they do this can be remarkable, but it still leaves some scope for
modification by experience.

For example, in some young animals unable to see with the right eye, the cells
that would normally respond to the left eye expand into the right’s territory.
Basic research shows that such changes can take place – or be reversed – only
during a “critical period” in early infancy. Assuming that the same applies in
human infants, squints or other forms of poor vision need treatment early,
before the pathways become irreversibly fixed.

Of course, human behaviour is remarkable for its flexibility – we can learn,
either from our elders and betters, or directly from experience. This
flexibility must have a direct counterpart in the brain, where memories and
skills are stored in the activity of networks of nerve cells. Scientists now
believe – although proving it is not easy – that the synaptic connections
between cells in these networks are constantly modified in response to the
activity of the network as a whole.

When it comes to compensating for serious damage, such as a head injury that
affects the brain, the nervous system has a more difficult problem. If their
target cells die, fully developed neurons can make new connections only up to
distances of a few micrometres, while cells in the brain or spinal cord whose
axons have been severed cannot grow new ones. Cells that lose their
connections eventually degenerate.

For someone who has lost skills, such as speech or the ability to make a cup
of tea, the only hope lies in training the brain to reach the same goals by
using other routes. Success in this kind of rehabilitation depends on the
skill of the trainers – it is unlikely to happen of its own accord.

Why should the most important part of the body be so helpless in response to
damage, while skin, bone and other tissues heal themselves with little
trouble? It seems that all the special signals that support the growth of
nerve cells and guide them during their development disappear as soon as the
system is complete, and without them reconnection is impossible.

In the long run, we may be better off this way. If the special features of the
developing brain persisted, the system might never become stable enough to
maintain the long-term connections that we need to function consistently.

The challenge faced by doctors and scientists today is not only to help
injured cells recover the potential for growth that they enjoyed in the
embryo, but to give them the right instructions for reconnection.

The neuron – the basic unit of the nervous system

NERVE CELLS, or neurons, consist of a cell body containing the nucleus and
other cellular machinery, usually with one long fibre or axon to carry their
electrical impulses to other cells.

Attached to the cell body is a mass of threadlike extensions – dendrites – to
receive incoming messages. At its tip the axon also branches into a number of
terminals or nerve endings. These form junctions, synapses, with the dendrites
or cell bodies of other cells.

The nerve cells communicate by releasing chemicals called neurotransmitters at
their synapses. These cross a tiny gap and bind to receptors on the membrane
of the next cell. This has the effect of either increasing or decreasing the
electrical excitability of that cell. If enough molecules of neurotransmitter
bind to a cell, it fires an impulse, a wave of electrical activity that passes
along the length of the axon.

When the impulse arrives at the nerve endings, they release their packets of
neurotransmitter, thereby passing information on in their turn. The simplest
of our thoughts or actions probably requires millions of these interactions to
take place.

Where you are, not where you came from

THE FRENCH embryologist, Nicole Le Douarin, carried out a series of ingenious
experiments showing that at the point when the basic plan of the nervous
system is being laid out in the embryo, its cells still keep their options
open. She took advantage of the fact that the nuclei of cells from a quail
embryo, stained for observation under a microscope, looked very different from
those of a chick. This meant that she could always trace quail cells
transplanted into a chick even if they had moved away from the site of
implantation.

Le Douarin transplanted a section of the neural tube from a quail embryo to
the neural tube of a chick embryo. The cells transplanted included those of
the neural crest, a region that originates in the neural plate but which is
left outside the tube as it closes. Some of these cells go on to form the
autonomic nervous system, which controls the internal environment by
monitoring such things as heart rate and the composition of the blood, and
taking whatever action is necessary to adjust them. It is also responsible for
the changes we recognise as belonging to the “fight or flight” response to
danger.

In the autonomic nervous system there are two branches, called the sympathetic
and the parasympathetic nervous systems, which have different but
complementary functions. The nerve cells in each system use a different
neurotransmitter to exert their effects: in the parasympathetic system it is
acetylcholine, and noradrenaline in the sympathetic.

Le Douarin took cells from the neck region of a quail embryo and transplanted
them to a position near the tail in a chick. She found that when the cells
matured, those that would have produced acetylcholine if they had stayed in
the neck, produced noradrenaline when transplanted.

In other words, in adopting their final identities the cells took their cue
from the environment in which they found themselves.

Further reading

In “Wired for thought” (91av, 28 August 1988), James Fawcett gave a
concise account of brain development.

For an elegant, readable and comprehensive treatment of the subject, see
Principles of Neural Development, by Dale Purves and Jeff Lichtman (Sinauer,
1985, £29.95).