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GROWTH FACTORS 295
Box 7.1. The nervous system revisited
Neurons constitute the communicative element of the nervous sytem, which consists of the central nervous system (CNS; the brain and spinal cord) and the peripheral nervous system (PNS; additional neuronal elements). Sensory neurons are those leading from a stimulus-detecting receptor cell, while motor neurons are those that normally carry on nerve impulses to an effector cell, often a muscle cell. Neurons, although varying in shape and size, consist of the nucleus-containing cell body (perikaryon), from which various elongated extensions (processes) emerge — the dendrites, which normally carry nerve impulses towards the perikaryon and the axon, the terminal branches of which form the junction (synapse) with the cell to which the nerve impulse will be transmitted.
The neuronal cytoskeleton provides the axon with mechanical support and is directly involved in the transport of materials from the cell body towards the synapse (anterograde transport) and in the opposite direction (retrograde transport). Axons are generally covered (insulated) with a myelin sheath, which is formed by oligodendrocytes (in the CNS) or Schwann cells (PNS).
During their initial development, immature neurons sprout outgrowths (neurites) representing axons or dendrites. At the tip of the neurite is the star-like growth cone, which helps guide the growing neurite towards its target tissue. The direction of growth of the developing axon seems to be directed (a) by guidance molecules resident on the surface of surrounding cells (cell adhesion molecules, CAMs) and (b) by soluble chemoattractants released from the target cell. Receptors for both of these types of guiding molecules are present on the growth cone surface. Failure of a developing axon to innervate the target tissue results in neuronal death.
Neurotrophic factors play a central role in development and maintenance of neuronal cells. After release from the target cells, they bind specific receptors on the nerve termini, are internalized and carried up the axon to the perikaryon by retrograde transport. This process helps guide the direction of neurite growth (i.e. a chemoattractant activity) during neuronal development, and also serves to ‘nourish’ the developing cell. Once established, the process of retrograde transport must continue if the cell is to survive and remain differentiated.
Neurotrophic factors released from target cell
Perikaryon of developing neuron
Retrograde transport of neurotrophic factors
Cell surface adhesion molecules CAMS
Table 7.10. Biochemical characteristic of the neurotrophin family of neurotrophic factors. Except for NT-6, the molecular masses quoted are those of the homodimeric structure, which represents their biologically active forms. See text for further details
Neurotrophin Molecular mass (kDa) pI Receptor type
NGF 26 10 Trk A
BDNF 27 10 Trk B
NT-3 27 9.5 Trk A, B, C
NT-4/5 28 10.8 Trk B
NT-6 15.9 10.8 ?
promote survival and stimulate growth of sensitive neurons, and accelerates neurotransmitter biosynthesis in most such cells. It also appears to stimulate growth and differentiation of B and T lymphocytes, thus potentially promoting cross-talk between the nervous and immune systems.
The restricted neuronal specificity of NGF suggested the existence of additional neurotrophic factors capable of influencing non-NGF-sensitive neuronal populations. Research efforts in the early 1980s led to the discovery of BDNF, a 119 amino acid (13.5 kDa) basic protein. In contrast to NGF, BDNF is predominantly localized within the CNS. Predictably, most BDNF-responsive neurons are located in (or project into) the CNS.
Studies (mainly in vitro) illustrate that BDNF promotes the survival of embryonic retina ganglion cells, dopaminergic neurons, as well as cholinergic neurons of the basal forebrain, embryonic spinal motor neurons and cortical neurons.
The synthesis of oligonucleotide primers, based upon conserved sequences between the NGF and BDNF genes, allowed researchers to fish for additional members of the neurotrophin family by PCR analysis. In 1991 this led to the discovery of neurotrophin 3 (NT-3), which is expressed early in — and throughout — embryogenesis. It supports the development of various neuronal populations in culture, although its role in vivo is less well understood.
Two additional neurotrophins, originally cloned from Xenopus and mammals, respectively, turned out to be counterparts, and this neurotrophin is now termed, NT-4/5. Mammalian NT-4/5 is quite similar to the other neurotrophins but exhibits its own unique neuronal target cell specificities. It is synthesized mainly in the prostate but also in skeletal muscle, placenta and the thymus.