| Summary: | During embryonic development, most cutaneous sensory neurons depend for their survival on a supply of NGF synthesised in the skin. NGF promotes survival by binding to the trkA receptor tyrosine kinase whose signalling is modulated by the common neurotrophin receptor p75. trkA is expressed shortly after axons reach their targets and NGF expression begins with the arrival of the earliest axons. The focus of the thesis was to investigate how these interactions between neurons and targets are regulated and to understand more fully how they control neuronal survival. To investigate if the induction and subsequent developmental changes in trkA mRNA expression seen in vivo are intrinsically regulated or dependent upon extrinsic signals, trigeminal ganglia at different stages of development where grown in culture and the expression levels of trkA assessed. The changes in trkA mRNA expression observed in vitro paralleled those observed in vivo, suggesting that trkA expression is regulated by an intrinsic programme in this ganglion. Paradoxically, the presence of the target-fields resulted in lower expression than seen in vivo. To investigate if the trigeminal ganglion influences NGF expression, the target field was cultured with and without trigeminal ganglia at different stages of development. NGF mRNA levels in very young target field explants increased to higher levels when grown with the ganglion compared with target field explants grown alone, raising the possibility that early target innervation influences NGF expression. This was further investigated by measuring the level of NGF mRNA in ErbB3-/- mice, which display a large, early decrease in the number of trigeminal neurons. Consistent with this possibility, the level of NGF mRNA was significantly lower in the early target fields of these embryos compared with wild types. However, the levels of NGF mRNA were not significantly higher in the targets fields of embryos in which the later period of naturally occurring neuronal death is reduced (Bax-/- and Bad-/- embryos) compared with wild type embryos.
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