The nervous system is the most complex of the organ systems in the animal embryo. ‘Nervous system’ shows that the nervous-system development can be divided into four major stages: the specification of neural cell identity; the outgrowth of axons to their targets; the formation of synapses with target cells, which can be other neurons, muscle or gland cells; and the refinement of synaptic connections through the elimination of axon branches and cell death. These stages are described with details of neuronal circuit formation and the links between sensory receptors, which receive signals from the outside world, and their targets in the brain that enable us to make sense of these signals.
The nervous system is the most complex of all the organ systems in the animal embryo. In mammals, for example, billions of nerve cells (neurons) develop a highly organized pattern of connections, creating the neuronal network that makes up the functioning brain and the rest of the nervous system. There are also an equivalent number of supporting cells (glia) such as Schwann cells, which insulate nerve cells. As we have seen, during gastrulation, the ectoderm in the dorsal region of the vertebrate embryo becomes specified as the neural plate and the neural plate forms the neural tube, from which the brain develops, while the spinal cord forms more posteriorly. The neural tube throws off neural crest cells, which migrate throughout the body to give rise to neurons and other cell types. The nervous system must develop in the correct relationship with other body structures, such as to the skeleton and muscular system, whose movement it controls.
The induction of neural tissue from ectoderm was first indicated by the Spemann organizer-transplant experiment in frogs. A partial secondary embryo develops when one small region, the Spemann organizer, of an early embryo is grafted onto another embryo at the same stage and a nervous system develops from the host ectoderm that would normally have formed ventral epidermis. An enormous amount of effort was devoted in the 1930s and 1940s to trying to identify the signals involved in neural p. 87↵induction in amphibians. A key discovery was the finding that the BMP (bone morphogenetic protein) inhibitor Noggin, the first secreted protein that was isolated from the Spemann's organizer, could induce neural differentiation in ectoderm explants from frog embryos. The results suggested that neural plate could only develop if BMP signalling is absent. These observations led to the so-called ‘default model’ for neural induction in the frog. This proposed that the default state of the dorsal ectoderm is to develop as neural tissue, but that this pathway is blocked by the presence of BMP, which promotes it to develop as epidermis. The role of the Spemann organizer is to lift this block by producing proteins that inhibit BMP activity. But the default model was not the complete answer, as neural development in both the frog and the chick also requires other proteins, even when BMP inhibition is lifted by the presence of Noggin. Neural induction is therefore a complex multistep process. An essential similarity in the mechanism of neural induction among vertebrates is likely, however, as Hensen's node from a chick embryo can induce neural gene expression in frog ectoderm, which suggests that the inducing signals have been conserved in evolution.
The nervous system is initially patterned by signals from the underlying mesoderm, and pieces of anterior mesoderm induce a head with a brain, whereas posterior pieces induce a trunk with a spinal cord. Both qualitative and quantitative differences in signalling by the mesoderm can account for antero-posterior neural patterning. Quantitative differences in protein signalling are present along the body axis, with the highest level at the posterior end of the embryo which gives prospective neural tissue a more posterior identity. Hox genes are expressed along the spinal cord and give neurons a positional identity.
There are many hundreds of different types of neurons, differing in identity and the connections they make, even though many may look quite similar (Figure 26). Neurons send out long processes from the cell body and these must be guided p. 88↵p. 89↵to find their targets. Neurons send electrical signals (the nerve impulse) down an extension (the axon) which can be very long and which signals to muscles and other neurons. Neurons connect with each other and with other target cells, such as muscle, at specialized junctions known as synapses. A neuron receives input from other neurons through its highly branched short extensions, and if the signals are strong enough to activate the neuron it generates a new electrical signal—a nerve impulse, or action potential—at the cell body. This electrical signal is then conducted along the axon to the axon terminal, or nerve ending, which makes a synapse with another neuron or with the surface of a muscle cell. A single neuron in the central nervous system can receive as many as 100,000 different inputs. At a synapse, the electrical signal is converted into a chemical signal, in the form of a chemical neurotransmitter such as acetylcholine, which is released from the nerve ending and acts on receptors in the membrane of the opposing target cell to generate or suppress a new electrical signal. The nervous system can only function properly if the neurons are correctly connected to one another, and thus a central question surrounding nervous-system development is how the connections between neurons develop with the appropriate specificity. The number of neurons in the human brain seems generally to be estimated at around 100 billion. How many of them have unique or similar identities is not known.
For all its complexity, the nervous system is the product of the same kind of cellular and developmental processes as those involved in the development of other organs. The overall process of nervous-system development can be divided into four major stages: the specification of neural cell identity; the outgrowth of axons to their targets; the formation of synapses with target cells, which can be other neurons, muscle or gland cells; and the refinement of synaptic connections through the elimination of axon branches and cell death (Figure 27).
p. 90p. 91↵Neurons are formed in the proliferative zone of the vertebrate neural tube from multipotent neural stem cells, which give rise to many different types of neurons and to glia. For many years it was thought that no new neurons could be generated in the adult mammalian brain, but the production of new neurons has been demonstrated as a normal occurrence in the adult mammalian brain, and neural stem cells have been identified in adult mammals that can generate neurons.
Future motor neurons are located ventrally, and form the ventral roots of the spinal cord. The neurons of the sensory nervous system develop from neural crest cells. The dorso-ventral organization of the spinal cord is produced by Sonic hedgehog protein signals from ventral regions such as the notochord. Sonic hedgehog forms a gradient of activity from ventral to dorsal in the neural tube, and acts as the ventral patterning positional signal. As well as being organized along the dorso-ventral axis, neurons at different positions along the antero-posterior axis of the spinal cord become specified to serve different functions. The antero-posterior specification of neuronal function in the spinal cord was dramatically illustrated some 40 years ago by experiments in which a section of the spinal cord that would normally innervate wing muscles was transplanted from one chick embryo into the region that normally serves the legs of another embryo. Chicks developing from the grafted embryos spontaneously activated both legs together, as though they were trying to flap their wings, rather than activating each leg alternately as if walking. These studies showed that motor neurons generated at a given antero-posterior level in the spinal cord had intrinsic properties characteristic of that position. The spinal cord becomes demarcated into different regions along the antero-posterior axis by combinations of expressed Hox genes. A typical vertebrate limb contains more than 50 muscle groups with which neurons must connect in a precise pattern. Individual neurons express particular combinations of Hox genes, which determine which muscle they will innervate. So all together, expression of genes resulting from p. 92↵dorso-ventral position together with those resulting from antero-posterior position confers a virtually unique identity on functionally distinct sets of neurons in the spinal cord.
The working of the nervous system depends on the formation of neuronal circuits, in which neurons make numerous and precise connections with each other. A feature of development that is unique to the nervous system is the outgrowth and guidance of axons, long extensions from the nerve cell's body to their final targets. An early event is the extension by the nerve cell of its axon, which is due to the growth cone located at the tip of the axon. The growth cone is specialized for both movement and for sensing its environment for guidance cues. The growth cone can continually extend and retract filopodia at its leading edge, making and breaking connections with the underlying substratum to pull the axon tip forward. The growth cone thus guides axon outgrowth, and is influenced by the contacts the filopodia make with other cells and with the surface over which it moves. In general, the growth cone moves in the direction in which its filopodia make the most stable contacts. In the chick embryo, when the motor neuron axons enter the developing limb bud they are all mixed up in a single bundle. At the base of the limb bud, however, the axons separate out. Even when the axon bundles are made to enter in reverse order, the correct relationship between motor neurons and muscles was achieved. However, many motor neurons make no connections and, as we shall see, they will die.
A complex task for the developing nervous system is to link up the sensory receptors that receive signals from the outside world with their targets in the brain that enable us to make sense of these signals. A characteristic feature of the vertebrate brain is the presence of topographic maps so that neurons from one region of the sensory nervous system project in an ordered manner to a specific region of the brain. The highly organized projection of neurons from the eye via the optic nerve to the brain is one of the best models we have to show how topographic neural projections p. 93↵are made. There are around 126 million individual photoreceptor cells in a human retina, and each of those photoreceptor cells is continuously recording a minute part of the eye's visual field; these signals must be sent to the brain in an orderly manner. Photoreceptor cells indirectly activate individual neurons whose axons are bundled together and exit the eye as the optic nerve; the optic nerve from each human eye, containing over a million neurons, maps in a highly ordered manner onto a specific region of the brain, the tectum (Figure 28). This occurs with a highly ordered correspondence between a position on the retina and one on the tectum. Each retinal neuron carries a chemical label that enables it to connect reliably with an appropriately chemically labelled cell in the tectum. It is thought that graded spatial distributions of a relatively small number of factors on the tectum cells provide positional information, which can be detected by the retinal axons. The spatially graded expression of another set of factors on the retinal axons would provide them with their own positional information. The development of the projection from the eye to the tectum could thus, in principle, result from the interaction between these two gradients. This map is initially rather coarse-grained, in that axons from neighbouring cells in the retina make contacts over a large area of the tectum. Fine-tuning of the map results from the withdrawal of axon terminals from most of the initial contacts, and requires neural activity due to normal vision. If a frog eye is rotated through 180 degrees, the axons find their way back to the tectum and then, for that eye, the frog's world is turned upside down.
Neuronal death is very common in the developing vertebrate nervous system; too many neurons are produced initially and only those that make appropriate connections survive. Some 20,000 motor neurons are formed in the segment of the spinal cord that provides connections to chick leg muscles, but about half of them die soon after they are formed. Survival of a motor neuron depends on its establishing contacts with a muscle cell. Once a contact is established, the neuron can activate the muscle, and this p. 94↵is followed by the death of a proportion of the other motor neurons that are approaching the muscle cell and do not make contact. Even after neuromuscular connections have been made, some are subsequently eliminated. At early stages of development, single muscle fibres are contacted by axons from several different motor neurons. With time, most of these connections are eliminated, until each muscle fibre is innervated by the axon terminals from just one motor neuron. This is due to competition between the synapses, with the most powerful input to the target cell destabilizing the less powerful inputs to the same target.