Intrinsic and extrinsic factors involved in the axonal growth rate of embryonic neurons
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The main aim of this project has been to study the extrinsic and intrinsic factors involved in the axonal growth rate of sensory and sympathetic neurons during the early stages of their development. Using in vitro assays it was shown that Hepatocyte Growth Factor (HGF)/Met signalling significantly enhanced the survival and neurite length of early DRG neurons grown in the presence of NGF. This synergism was specific for NGF but not for the related neurotrophins BDNF or NT-3 (Maina et al., 1997). HGF/Met signalling was also shown to accelerate the differentiation of sympathetic neurons as well as promoting the survival of sympathetic neuroblasts but not postmitotic neurons. HGF was also shown to cooperate with NGF to enhance the axonal growth rate as well as increasing the amount of neurite branching of NGF- dependent sympathetic neurons throughout development (Maina et al., 1998). HGF was also shown to enhance the survival and growth of developing parasympathetic and proprioceptive neurons. The demonstration that HGF only enhanced the survival and growth of proprioceptive TMN neurons when grown in CNTF but not when grown in BDNF which promoted their survival as effectively as CNTF demonstrates that within the same neurons, the effects of HGF on survival and growth are selectively dependent on which other signalling pathways are concurrently activated. The anti-apoptotic protein Bcl-2 has been shown to play a key role in regulating cell survival in the nervous system. Cultured neurons expressing antisense Bcl-2 RNA have an attenuated survival response to neurotrophins, and neurons of postnatal Bcl-2 deficient mice die more rapidly following NGF deprivation in vitro and are present in reduced numbers in vivo. Here I show that Bcl-2 also plays a key role in regulating axonal outgrowth rates in embryonic neurons (Hilton et al., 1997). The effect of Bcl-2 on axonal growth rate was shown not to be a consequence of its well documented role in preventing apoptosis.
Thesis, PhD Doctor of Philosophy
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