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//LINEAGE AND GROWTH IN THE NERVOUS SYSTEM

LINEAGE AND GROWTH IN THE NERVOUS SYSTEM

Neurones come from three embryonic sources: CNS neurones originate from the pluripotential neural plate and tube, whereas ganglionic neurones originate from the neural crest and ectodermal placodes. The neural plate also provides ependymal and macroglial cells. Peripheral Schwann cells and chromaffin cells arise from the neural crest. The origins and lineages of cells in the nervous system have been determined experimentally by the use of autoradiography, microinjection or retroviral labelling of progenitor cells, and in cell culture.

During development, neurones are formed before glial cells. The timing of events differs in various parts of the CNS and between species. Most neurones are formed prenatally in mammals but some postnatal neurogenesis does occur, e.g. the small granular cells of the cerebellum, olfactory bulb and hippocampus, and neurones of the cerebral cortex. Gliogenesis continues after birth in periventricular and other sites. Autoradiographic studies have shown that different classes of neurones develop at specific times. Large neurones such as principal projection neurones tend to differentiate before small ones such as local circuit neurones. However, their subsequent migration appears to be independent of the times of their initial formation. Neurones can migrate extensively through populations of maturing, relatively static cells, to reach their destination, e.g. cerebellar granule cells pass through a layer of Purkinje cells en route from the external pial layer to their final central position. Later, the final form of their projections, cell volume and indeed their continuing survival, depend on the establishment of patterns of functional connection.

Initially immature neurones are rotund or fusiform. Their cytoplasm contains a prominent Golgi apparatus, many lysosomes, glycogen and numerous unattached ribosomes. As maturation proceeds, cells send out fine cytoplasmic processes which contain neurofilaments, microtubules and other structures, often including centrioles at their bases where microtubules form. Internally, endoplasmic reticulum cisternae appear and attached ribosomes and mitochondria proliferate, whereas the glycogen content progressively diminishes. One process becomes the axon and other processes establish a dendritic tree. Axonal growth, studied in tissue culture, may be as much as 1 mm per day.

Growth cones

Ramón y Cajal (1890) was the first to recognize that the expanded end of an axon, the growth cone, is the principal sensory organ of the neurone. Classically, the growth cone is described as an expanded region that is constantly active, changing shape, extending and withdrawing small filopodia and lamellipodia that apparently ‘explore’ the local environment for a suitable surface along which extension may occur. These processes are stabilized in one direction, determining the direction of future growth, and following consolidation of the growth cone, the exploratory behaviour recommences. This continuous cycle resembles the behaviour at the leading edge of migratory cells such as fibroblasts and neutrophils. The molecular basis of this behaviour is the transmission of signals external to the growth cone via cell surface receptors to the scaffolding of microtubules and neurofilaments within the axon. Growing neuroblasts have a cortex rich in actin associated with the plasma membrane, and a core of centrally located micro-tubules and sometimes neurofilaments. The assembly of these components, along with the synthesis of new membrane, occurs in segments distal to the cell body and behind the growth cone, though some assembly of microtubules may take place near the cell body.

The driving force of growth cone extension is uncertain. One possible mechanism is that tension applied to objects by the leading edge of the growth cone is mediated by actin, and that local accumulations of F-actin redirect the extension of microtubules. Under some culture conditions, growth cones can develop mechanical tension, pulling against other axons or the substratum to which they are attached. Possibly, tension in the growth cone acts as a messenger to mediate the assembly of cytoskeletal components. Adhesion to the substratum appears to be important for consolidation of the growth cone and elaboration of the cytoskeleton in that direction.

During development, the growing axons of neuroblasts navigate with precision over considerable distances, often pursuing complex courses to reach their targets. Eventually they make functional contact with their appropriate end organs (neuromuscular endings, secreto-motor terminals, sensory corpuscles or synapses with other neurones). During the outgrowth of axonal processes the earliest nerve fibres are known to traverse appreciable distances over an apparently virgin landscape, often occupied by loose mesenchyme. A central problem for neurobiologists, therefore, has been understanding the mechanisms of axon guidance (Gordon-Weeks 2000). Axon guidance is thought to involve short-range, local guidance cues and long-range diffusible cues, any of which can be either attractive and permissive for growth, or repellent and hence inhibitory. Short-range cues require factors which are displayed on cell surfaces or in the extracellular matrix, e.g. axon extension requires a permissive, physical substrate, the molecules of which are actively recognized by the growth cone. They also require negative cues which inhibit the progress of the growth cone. Long-range cues come from gradients of specific factors diffusing from distant targets, which cause neurones to turn their axons towards the source of the attractive signal. The evidence for this has come from in vitro co-culture studies. The floor plate of the developing spinal cord exerts a chemotropic effect on commissural axons that later cross it, whereas there is chemorepulsion of developing motor axons from the floor plate. These forces are thought to act in vivo in concert in a dynamic process to ensure the correct passage of axons to their final destinations and to mediate their correct bundling together en route.

Dendritic tree

Once growth cones have arrived in their general target area, they then have to form terminals and synapses. In recent years, much emphasis has been placed on the idea that patterns of connectivity depend on the death of inappropriate cells. Programmed cell death or apoptosis occurs during the period of synaptogenesis if neurones fail to acquire sufficient amounts of specific neurotrophic factors. Coincident firing of neighbouring neurones that have found the appropriate target region might be involved in eliciting release of factor(s), thus reinforcing correct connections. Such mechanisms may explain the numerical correspondence between neurones in a motor pool and the muscle fibres innervated. On a subtler level, pruning of collaterals may give rise to mature neuronal architecture. The projections of pyramidal neurones from the motor and visual cortex, for example, start out with similar architecture: the mature repertoire of targets is produced by the pruning of collaterals leading to loss of projections to some targets.

The final growth of dendritic trees is also influenced by patterns of afferent connections and their activity. If deprived of afferents experimentally, dendrites fail to develop fully and, after a critical period, may become permanently affected even if functional inputs are restored, e.g. in the visual systems of young animals which have been visually deprived. This is analogous to the results of untreated amblyopia in infants. Metabolic factors also affect the final branching patterns of dendrites, e.g. thyroid deficiency in perinatal rats results in a small size and restricted branching of cortical neurones. This may be analogous to the mental retardation of cretinism.

Once established, dendritic trees appear remarkably stable and partial deafferentation affects only dendritic spines or similar small details. As development proceeds plasticity is lost, and soon after birth a neuron is a stable structure with a reduced rate of growth.

Neurotrophins

If neurones lose all afferent connections or are totally deprived of sensory input, there is atrophy of much of the dendritic tree and even the whole soma. Different regions of the nervous system vary quantitatively in their response to such anterograde transneuronal degeneration. Similar effects occur in retrograde transneuronal degeneration. Thus neurones are dependent on peripheral structures for their survival. Loss of muscles or sensory nerve endings, e.g. in the developing limb, will result in reduction in numbers of motor and sensory neurones. Specific factors which these target organs produce, such as the neurotrophins, are taken into nerve endings and transported back to the neuronal somata: they are necessary for the survival of many types of neurone during early development, and for the growth of their axons and dendrites, and also promote the synthesis of neurotransmitters and enzymes.

The neurotrophins, nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3) and NT-4/5 exert their survival effects selectively on particular subsets of neurones. NGF is specific to sensory ganglion cells from the neural crest, sympathetic postganglionic neurones and basal forebrain cholinergic neurones. BDNF promotes the survival of retinal ganglion cells, motor neurones, and some placode-derived neurones, such as those of the nodose ganglion, that are unresponsive to NGF. NT-3 has effects on motor neurones, limb proprioceptive neurones and both placode and neural crest-derived sensory neurones. Other growth factors found to influence the growth and survival of neural cells include the fibroblast growth factors (FGFs) and ciliary neurotrophic factor (CNTF), all of which are unrelated in sequence to the NGF family. Members of the FGF family support the survival of embryonic neurones from many regions of the CNS. CNTF may control the proliferation and differentiation of sympathetic ganglion cells and astrocytes.

Each of the neurotrophins binds specifically to certain receptors on the cell surface. The receptor termed p75NTR binds all the neurotrophins with similar affinity. By contrast, members of the family of receptor tyrosine kinases (Trks) bind with higher affinity and display binding preferences for particular neurotrophins. However, the presence of a Trk receptor seems to be required for p75NTR function.

Nervous tissue influences the metabolism of its target tissues. If during development a nerve fails to connect with its muscle, both degenerate. If the innervation of slow (red) or fast (white) skeletal muscle is exchanged, the muscles change structure and properties to reflect the new innervation, indicating that the nerve determines muscle type and not vice versa.

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