Neurotrophins in Development of the Nervous System

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Development of the nervous system requires a massive production of neurons and glial cells. These cells need to be generated, migrate to their appropriate positions and form a vast number of connections. Thus, new cells are continuously being born and new connections are being established. All these events are additive and cumulate during development. In parallel to this construction, there are also regressive events, both by a remodelling and elimination of connections initially formed and by a widespread death of neurons during a restricted embryonic period occurring shortly after target innervation. In many instances, more than half the neurons init ially formed die by apoptosis. This phenomenon is described as programmed cell death and is believed to be a fundamental process ensuring that target cells are innervated by the correct number and type of neurons. Early work of Victor Hamburger and Rita Levi-Montalcini in the 1930s and 1940s led to the finding that extirpation of a peripheral target field of neurons (the wing bud in the chick) during development results in excessive loss of innervating sensory and motor neurons. Conversely, it was later shown that enlargement of the target field reduces the loss of neurons during the period of programmed cell death. The discovery of programmed cell death during development came together with the concept that the size of the target determines neuronal numbers. Pioneering work on the identification and characterization of the neurotrophic factor nerve growth factor (NGF) led to a proposal explaining the effects of target enlargement and limb extirpation; namely, that the target fields regulate their synaptic innervation density retrogradely, by the secretion of soluble survival-inducing factors that are present in limiting amounts. Thus, neurotrophic factors are key molecules during programmed cell death in the nervous system; being retrograde survival messengers responsible for eliminating all unwanted and unnecessary neurons by programmed cell death. This elimination is caused by the unsuccessful competition for limited amounts of survival factors (Fig. 1).