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Models and Methods for Studying Neural Development

1.1 What is neural development?

Neural development is the process by which the nervous system grows from its first beginnings in the embryo to its completion as a mature functioning system. The mature nervous system contains two classes of specialized and closely interacting cells: neurons and glia. Neurons transmit signals to, from and within the brain: their axons transmit electrical signals and they communicate with other cells via synapses. There are many types of neuron with specialized shapes and functions, with cell bodies that vary in diameter from only a few micrometers to around 100 micrometers and with axons whose lengths vary from a few micrometers to more than 1 meter. There are also different types of glial cell. The interactions between neurons and glia are very precise and they allow the nervous system to function efficiently. Figure 1.1 shows a beautiful example of the complex structures created by interacting neurons and glia, in this case a microscopic view of a labelled node of Ranvier, which allows rapid signalling in the nervous system.

Figure 1.1 A node of Ranvier: these highly organized structures, formed as a result of interactions between axons and glia, are essential for speeding up the transmission of electrical signals along axons. In this single fibre from the mouse spinal cord, sodium channels (blue) are sandwiched between the regions where axons and glia form junctions (called axoglial junctions) (green), which are, in turn, flanked by potassium channels (red). This picture is courtesy of Peter Brophy and Anne Desmazieres, University of Edinburgh, UK.

The great molecular, structural and functional diversity of neurons and glia is acquired in an organized way through processes that build on differences between the relatively small numbers of cells in the early embryo. As more and more cells are generated in a growing organism, new cells diversify in specific ways as a result of interactions with pre-existing cells, continually adding to the organism's complexity in a highly regulated manner. The development of an organism is a bit like the development of human civilization (allowing for the obvious difference that organismal development repeats over and over again). In both, population size and sophistication (be it humans on earth or cells in an organism) grow hand-in-hand, each stage adding further layers of complexity to previously generated structures, functions and interactions. The mechanisms that regulate cellular actions and interactions during development are often described using terms commonly applied to human activities. We shall highlight this at several places throughout the book where analogies might be helpful.

To understand how organisms develop we need to know how cells in each part of the embryo develop in specific and reproducible ways as a result of their own internal mechanisms interacting with an expanding array of stimuli from outside the cell. Many laboratories around the world are researching this area. Why?

1.2 Why research neural development?

1.2.1 The uncertainty of current understanding

One reason for researching neural development is that we still know relatively little about it. In this book we shall try to explain some of the main events that occur during neural development and, in particular, the mechanisms by which those events are brought about, in so far as we understand them. It is important, however, to appreciate that much of what we present, particularly our understanding of molecular mechanisms, is best thought of as continually evolving hypotheses rather than established facts. The biologist Konrad Lorenz once stated that 'truth in science can be defined as the working hypothesis best suited to open the way to the next better one'; this is highly appropriate in developmental neurobiology.

Some of our understanding is incomplete or may be shown by future experiments to be inaccurate. We have tried to highlight issues of particular uncertainty or controversy and to indicate the limits of our knowledge, since it is at least as important and interesting to acknowledge what we do not know as it is to learn what we do know. Much of the excitement of developmental neurobiology arises from the mystery that surrounds Nature's remarkable ability to create efficiently and reproducibly neural structures of great power.

One reason that we still know relatively little about the mechanisms of neural development is the sheer size and complexity of the finished product in higher animals. During the development of the human brain, for example, about 100 billion cells are generated with about 1000 trillion connections between them; if this number of connections is hard to visualize then consider that it might roughly equal the number of grains of sand on a small beach. Although cells and connections with similar properties can be grouped together, there is still great variation in their molecular make-ups, morphologies and functions throughout the nervous system. In reading this book you will see that many of our hypotheses about neural development are formulated at the level of tissues or populations of cells rather than individual cells and their connections, particularly in higher mammals. Only in very simple organisms containing a few hundred neurons (e.g. in some worms) do we fully understand where each cell of the adult nervous system comes from and even then we do not know for sure what mechanisms determine how each cell and its connections develop. We still have a long way to go to gain a profound understanding of the molecular and cellular rules that govern the emergence of cells of the right types in the right numbers at the right places with the right connections between them functioning in the right ways.

1.2.2 Implications for human health

Just because we do not know much about a subject is not sufficient reason to want to invest time and resources in researching it further. However, there are many practical reasons for wanting to know more about the ways in which the nervous system develops. A better understanding should help us to tackle currently incurable diseases of the nervous system. Many congenital diseases affect neural development1 but their causes are often unknown; some examples of such diseases will be given later in this and in subsequent chapters. Numerous relatively common psychiatric and neurological diseases, such as schizophrenia, intellectual disabilities, autisms and some forms of epilepsy (Figure 1.2), are now thought to have a developmental origin, but the mechanisms are poorly understood. Knowledge of how cancers form should be helped by a better understanding of normal development; the uncontrolled growth of cancer cells is often attributed to abnormalities of the same molecules and mechanisms that control growth during normal development. Regarding the development of possible new treatments, it has been suggested that a diseased brain might be repaired by replacing dysfunctional genes or implanting new cells into the nervous system. Implanted cells would need to recapitulate a developmental programme allowing their survival and functional integration into the nervous system and its circuitry. How this might be achieved is currently unclear, but research on normal developmental mechanisms might help.

Figure 1.2 Schizophrenia, intellectual disabilities, autisms and epilepsies are neurological disorders affecting about 3-7% of people. Based on epidemiological and neurobiological evidence, schizophrenia is now believed to be a neurodevelopmental disorder with a large heritable component. Many possible susceptibility genes have been identified, but how abnormalities of these genes cause the symptoms of the disease is unknown. Similarly, autism spectrum disorders and intellectual disabilities are highly heritable and many of the known genetic causes seem to regulate the formation of synapses. Malformations of cerebral cortical development are among the commonest causes of epilepsy. Some are large defects that would be obvious to the naked eye whereas others would only be seen at a microscopic or molecular level. They are a consequence of a disruption of the normal steps of cortical formation, for example defective migration of neurons, and can be environmental or genetic in origin. A large number of malformations of cortical development have been described, each with characteristic pathological and clinical features. An example of a large congenital defect causing epilepsy is shown in the scan of a patient's brain on the right (between the arrows): for comparison, a scan of the brain of a normal person is shown on the left. This picture is courtesy of Professor John S. Duncan and the National Society for Epilepsy MRI Unit, UK.

1.2.3 Implications for future technologies

Another, perhaps unexpected, motivation for understanding how the brain develops comes from the drive to revolutionize computer technology, to improve robotics and to generate autonomous machines able to make decisions. The application of current manufacturing methods to build much more complex computers than exist at present will need to overcome exponential increases in the production cost of ever smaller and faster circuits. In contrast, evolution has produced brains of enormous computing power that self-construct with great efficiency. Can lessons...