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The nervous system consist of many types of neurons that differ structurally and

biochemically in feamres such as shape, pattern of connectivity, neurotransmitter, receptors and channels. In addition, neurons display remarkable plasticity both during development and during the subsequent remodelling of synaptic connection. During development, the neural crest cells from which sensory neurons are derived are also the precursors for a large number of other cellular phenotypes including the neurons and glia cells of the sympathetic and parasympathetic nervous system, the adrenaline producing cells (medulla) of the adrenal glands, the pigment containing cells of the epidermis and skeletal and connective tissue components of the head (in Gilbert, 1994).

While the molecular mechanisms involved in this process are not fully understood, a number of factors which influence cell commitment and differentiation have been identified and widely studied. These include (i) the pattern of the crest cells migration, (ii) the local neuronal environment determined by trophic factors which are encountered by the growth cone of the developing neuron, (hi) the expression of structural and secretory proteins which mediate growth cone development and (iv) migration of the neurite and

establishment of functional synaptic complexes (Black. 1984).

Although the mechanisms for generating the complexity and diversity of nervous system are not fully understood it is possible that an interplay of environmental factors and intrinsic changes in the expression pattern of factors within the cells may determine cell fate

(Anderson, 1994). This is achieved by a precise and highly regulated process which involves the expression and combinatorial interactions of a large number of transcription factors with diverse sequence specific interactions which are modified in response to a variety of environmental cues and intracellular signals at any point in this process (Johnson

and Me Knight, 1989; Kessel and Gruss,1990; He and Rosenfeld, 1991; Stnihl, 1991; Scholer, 1991; Treacy and Rosenfeld, 1992).

The detection of Bm-3a in the neural plate at during early development, together with the restricted distribution at later stages suggests a role in cell commitment. Furthermore, the presence of Bm-3a, Bm-3b and Brn-3c in the sensory neurons of the dorsal root gangha and trigeminal gangha and their homology to unc-86, a determinant of neuronal specificity in the nematode, imply that they may have an important role in the development and function of these cells.

Regulatory factors such as the Bm-3 proteins may control the expression of specific proteins which are involved in ceU commitment during development. One strategy of identifying the target genes modulated by these proteins may be to study proteins which show a similar pattern of expression to the Bm-3 proteins and which contain the DNA recognition sequences for these proteins in their promoters. A number of such factors have been investigated as possible targets and the results are discussed in chapter 5. A brief outhne of the expression and the putative functions of groups of these proteins which may have a role in determining the development and differentiation of sensory neurons will be given to clarify aspects of this process and to highhght the areas of interest in this study.

1.4.1

Trophic Factors and Neuronal Development

During development of the nervous system, cells acting as targets for developing neurons produce limiting amounts of specific molecules, termed neurotropins, which are required for the survival of the neurons and for which the nerve terminals appear to compete (Barde, 1989; Oppenheim, 1991; Anderson, 1993). In the target field, competition for hmited quantities of neurotropins result in the survival of some neurons while others are ehminated by apoptosis, a process which occurs during the period immediately following the arrival of the axons (Martin et ai, 1988; Johnson and Deckworth, 1993; jOppeinheim, 1994).

Neurotropins so far charactrized include; Nerve Growth Factor (NGF), Brain Derived Neurotrophic factor (BDNF), neurotropin 3 (NT-3) and ciliary neurotropic factor (CNTF) (Barde, 1989; DiCicco-Bloom e ta l, 1993; Emfors et a l , 1994 Barbacid, 1995). The neurotropins and other factors such as Fibroblast Growth Factor (FGF) and platelet derived growth factor (PDGF) appear to have a variety of actions on their physiological targets which include the sympathetic and sensory neurons including promoting neuronal survival (Lindsay, 1988; Davies e ta l, 1991; Emfors e ta l. 1994; Barbacid, 1995). These factors have been shown to profoundly affect the expression of a number of transcription factors. This is illustrated by the NGF treatment of PCI2 cells which causes a rapid induction of immediate-early genes encoding transcription factors such as c-Fos and NGFIA (Milbrant, 1986; Sheng and Greenberg, 1990; Armstrong and Montminy, 1993; Kendall et a/.,1995). Similarly in sensory neurons, NGF has been shown to regulate the expression of the neuronal Oct-2 proteins (Wood etal, 1992; Kendall etal , 1995).

While neurotrophic factors such as NGF are required by a subpopulation of neural crest derived neurons for survival during development, in the post-natal period NGF appears to be more important for the normal biochemical function of sensory neurons (Johnson et a l,

1986; Lindsay, 1988, Ruitt e t a l , 1992; Kang and Schuman, 1995). During development, an important process which the trophic factors play a role in is mediating the promotion and maintainance of neurite outgrowth and axonal arborization. A brief discussion of the

mechanism by which NGF achieves this effect will be given since it underlies a number of other changes accompanying process formation in the maturing neuron.