What is the most intriguing question of all is whether the brain is powerful enough to solve the problem of its own creation (Eichele 1992
Fifty-two years since the structure of DNA was elucidated and 140 years since Mendel first recognized the principle of genetic inheritance, the importance of DNA and the genetic code for making us who we are is almost universally recognized. We understand the genetic basis of several diseases and developmental disorders and we are learning more every day. Yet, even now, it is almost impossible to connect genes with behaviour. This is because there are many complex steps between the regulation of the specific genes that are turned on in particular cells and the behavioural repertoire that an animal becomes capable of and the behaviours that it engages in.
Despite this complexity, studies of two simple kinds of behaviour, movement and detection of specific stimuli like heat, touch and pain, have made considerable progress. Partly, this is because these behaviours can be studied in simpler vertebrates such as the lamprey, frog and zebrafish and partly it is because both of these behaviours are firmly rooted in the spinal cord. The spinal cord is the part of the vertebrate central nervous system that extends down the back inside the vertebral column. The spinal cord is a much simpler structure than the brain, and it is therefore much easier to study and understand.
Understanding how the spinal cord is made and functions is an ambitious and interesting goal in its own right, but it is also crucial if we are to develop effective treatments for people with spinal cord injuries or neurological diseases. If we can understand how particular neural circuits normally develop and function we can start to try and rebuild damaged circuits, replace particular nerves damaged by disease or injury, and hopefully finally understand why degenerative diseases often affect specific neural cell types. In addition, as we learn more about these basic behaviours our findings will also provide a foundation for studying more complex behaviours and neural functions.
To understand how the spinal cord becomes capable of controlling movements and perceiving different sensory inputs we need to understand how different cell types in the spinal cord are generated. The nervous system consists of two major types of cell: neurons and glia. In this review, I will concentrate on how genes regulate the development of different types of spinal cord neurons. Neurons are the cells that constitute the nerves in the body and they are responsible for gathering, consolidating and transmitting information within the nervous system. Neurons have a unique specialized cell morphology. They each extend a long protrusion called an axon that sends signals to other cells and they also extend numerous short processes called dendrites that branch out from the cell in a tree-like fashion and receive signals from other neurons. Several different classes of neurons exist in the spinal cord. Each of these has several characteristic properties which include which genes it expresses (turns on), its cell body size and shape, the length and direction of its axonal projection, its pattern of dendrites, its complement of specific ion channels (protein complexes that control ions entering and leaving the cell and which are important for electrical and chemical signalling within the neuron), the chemical signals (called neurotransmitters) that it uses, the chemical signals that it can detect (via neurotransmitter receptors) and its electrical activity during specific behaviours.
The neurons that we know most about are the neurons that communicate with muscles, which are called motoneurons. There are only a few different types of motoneuron and these can be easily identified in developing embryos and adults as they extend axons out of the central nervous system to distinct muscle territories. This has enabled researchers to correlate relatively easily the molecular phenotypes of specific motoneurons (which genes they express) with their morphologies and functions (which muscles they extend their axons to). We have learnt an amazing amount about how motoneurons are made and in particular which genes motoneurons express at different stages of their development and how this is regulated (for reviews see Jessell 2000
; Shirasaki & Pfaff 2002
; Lewis & Eisen 2003
). Excitingly, these findings are comprehensive enough that they have enabled researchers to grow motoneurons from stem cells (Wichterle et al. 2002
While considerable progress has been made in understanding motoneuron development and function, most of the neurons in the spinal cord and brain are interneurons. Interneurons are nerve cells whose cell body and axon resides entirely within the spinal cord and brain, which makes it much harder to distinguish different types of interneurons from one another. Until now, studies of interneurons have occurred within different Biological disciplines: Systems Neuroscientists have analysed interneuron physiology and function and Developmental Biologists have investigated how cells are instructed (specified) to make different types of interneurons. These approaches have traditionally used different criteria to identify distinct classes of interneurons. Developmental Biologists have, generally, classified interneurons on the basis of which genes they express, whereas Systems Neuroscientists have classified interneurons on the basis of their morphology, electrical activity and expression of specific neurotransmitters. Both groups of scientists also consider the position of interneurons within the spinal cord, but Systems Neuroscientists usually study adults whereas Developmental Biologists study embryos. Since many interneurons migrate after they are generated in the embryo, in most cases it is still unclear how the interneurons that Developmental Biologists study are related to the interneurons that Systems Neuroscientists study. However, recent progress has been made in this area as Developmental Biologists have started to study the morphology and functional characteristics of interneurons that express particular genes and Systems Neuroscientists have started to determine which genes different functional populations of interneurons express.
In this review, I will describe what we currently know about how different types of neurons are specified in the vertebrate spinal cord and how these Developmental Biology studies are beginning to connect up with studies of neuronal physiology and function. I will concentrate on interneurons, but occasionally I will use examples from motoneuron development as our more extensive knowledge in this area often suggests mechanisms that may also be important for interneuron development. I will focus on how cells are specified along the dorsal–ventral axis of the spinal cord. Recent work has started to elucidate how distinct motoneuron subtypes are specified at different antero-posterior positions in the embryo (e.g. Dasen et al. 2003
; Sockanathan et al. 2003
; Lewis & Eisen 2004
), but there is still very little information about the extent to which interneuron subtypes differ along this axis and the mechanisms that may be involved in this.
In the first part of this review (§2
), I will describe the distinct molecular classes of interneurons that have been identified in the embryonic vertebrate spinal cord. I will also summarize the current state of knowledge about how specific signalling pathways regulate the formation of these cells. Homeodomain and basic helix-loop-helix (bHLH) transcription factors play a key role in the specification of different interneurons and I will discuss the regulation and function of these transcription factors in §3
. In §4
, I will discuss the degree to which a correspondence between molecularly distinct interneurons and interneurons with specific morphologies and functions has been established. Further progress in understanding mammalian spinal cord development is hindered by the sheer complexity of the mammalian nervous system. In this light, I will go on to discuss how we can utilize simpler vertebrates, in parallel with studies in mammals, to build and expand upon our existing knowledge base. Section 5
specifically discusses the use of zebrafish as a model organism for studying spinal cord development and function. Finally, in §6
, I will discuss possible future directions in the quest to elucidate the complete genetic programme that regulates the formation and specific functions of spinal cord neural circuitry.