EPIDEMIOLOGÍA DE LA RUPTURA PREMATURA DE

Neuronal cell survival and development is dependent upon neurotrophins which are produced by target cells (for review see Barbacid, 1995). These neurotrophins, including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophic factor-3 (NT-3), neurotrophic factor-4/5 (NT-4/5) and neurotrophic factor-6 (NT-6) promote the survival of certain neurons so they are matched to the specific target cells from which they are expressed. Studies of neurotrophin “knockout” mice have demonstrated that different neurotrophins are concerned with the survival of distinct neuronal cell populations (Crowley et al., 1994; Emfors et al.,

1994a; 1994b). Mice lacking NGF show loss of sensory and sympathetic neurons but have normal populations of basal forebrain cholinergic neurons implying that other neurotrophins do not compensate for the absence of NGF during the development of particular subsets of neurons (Crowley et al., 1994). Many nerve cells embark upon development and a proportion undergo apoptosis once their target cells have been reached. In the case of sensory neurons, more than half of the developing neurons apoptose (Barde, 1989; Hamburger, 1993). The production of neurotophins ensures that each target cell forms a synapse with an appropriately developed neuron and when this arrangement has been made then apoptosis is induced in the redundant neurons (for review see Heymach and Barres, 1995). It has been shovm that cultured sensory neuronal survival is enhanced by the presence of NGF and removal induces major cell death (Barde, 1989; Hamburger, 1993). The mechanisms of this effect are unknown although transcription factors have been identified which are regulated by NGF in PC12 cells (Milbrandt, 1987; Oppenheim, 1991). NGF has also been shown to upregulate the expression of the POU-protein Oct 2 in sensory neurons (Wood et al.,

1992; Kendall et al., 1995).

Work has shown that developing neurons also produce neurotrophins which enhance their own survival and development (Emfors et al., 1990; Schecterson and Bothwell, 1992). This autocrine signalling would allow for neurons to develop without the reliance on target cell neurotrophin production and may aid in neuronal regeneration after injury. Once a target cell has been reached, and a synapse established, it appears that neuronal cells continue to need factors for survival. Cultured adult neurons have been shown to express both BDNF receptors and BDNF

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itself implying that the adult neuron is capable of self-survival (Emfors et al., 1990; Schecterson and Bothwell, 1992). Also glial cells which mainly develop after target innervation, may provide additional neuronal survival factors (Heumann et a l, 1987).

Neuronal development appears to involve many factors which interact to promote cell survival or cell death depending upon the requirements of the target cell. Many of these factors have been studied but the mechanisms of such cell-specific gene regulation remains unknown. The identification of the transcription factors responsible for these mechanisms will be important in the understanding of such precise, cell- specific gene regulation.

1.3,3 Neuronal Differentiation

Neuronal cells differentiate to enable the transport of nerve impulses to target cells. Neuronal differentiation involves the formation of neurites which must be able to retain a stable structure but also show mobility during growth to reach the target field. This stability and the formation of a growth cone is regulated by factors such as NGF. Studies which withdraw NGF from neuronal cultures show that neurite outgrowth cannot be maintained (for review see Anderson, 1993). Proteins which are involved in maintaining the neuronal cell structure will be discussed.

Neuronal differentiation occurs in two phases. The initial phase involves the formation of processes which elongate by using actin and myosin for growth cone locomotion, and microtubules and microtubule associated proteins (MAPs) which aid in the movement of proteins synthesised in the cell body to the developing axon terminus (for review see Mandelkow and Mandelkow, 1995). The second phase involves the increase in axonal diameter by rearrangement of microtubules and MAPs, and neurofilament accumulation to form the abundant cytoskeleton (for review see Cleveland, 1996). Differentiating neurones also contain structural proteins which maintain the cellular structure during development, e.g. vimentin, a-intemexin and keratins (for reviews see Fuchs and Weber, 1994; Klymkowsky, 1995).

Growth associated protein-43 (GAP-43) has been identified as being in involved in growth cone structure and aids in the formation of axonal tips during elongation (Strittmatter et al., 1990; Baetge and Hammang, 1991). This protein is

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expressed at high levels during neuronal development and following peripheral nerve injury (Strittmatter et a l, 1992). Protein levels decrease in mature neurons implying that GAP-43 is associated with neuronal differentiation (Strittmatter et al., 1990; Baetge and Hammang, 1991).

To reach the desired target field, which may be some distance from the neuronal cell body, the developing neurites cross many surfaces. To enable elongation over such distances, the neurites must anchor themselves by using cell adhesion molecules (CAM), such as neuronal-CAM (N-CAM). These molecules are present in the neuronal growth cone and interact with CAMs present in other axons and non­ neuronal cells which are in the pathway of the developing neuron. CAMs are proposed to also induce neurite outgrowth although the precise mechanisms are unknown. Several secondary messenger pathways involving; (1) calcium (Williams et at., 1994b) and (2) the FGF receptor (O’Brien, 1995; Williams et a l, 1995) have been established but the full picture is not yet clear.

Environmental factors also can influence the movement of these developing neurites, e.g. the presence of collapsin induces growth cone collapse (Luo et al., 1993) and netrins which attract neuronal outgrowth (Serafim et al., 1994).

In summary, the developing neuron expresses many different proteins which are required for neuritic outgrowth. Such expression is mediated by transcription factors which tightly regulate gene expression in response to environmental factors which influence the fate of the neuronal cell.