Neurotrophin switching in developing sensory neurons

The main aim of this project was to define the neurotrophin survival requirements of sensory neurons during the early stages of their development both in vivo and in vitro. The in vitro survival of neural crest-derived but not placode-derived cranial sensory neurons is promoted by several different neurotrophins early in their development. Neural crest-derived neurons subsequently lose responsiveness to all neurotrophins except NGF. Loss of responsiveness of neural crest-derived sensory neurons to BDNF and NT3 is associated with a marked shift in the dose responses of these neurons to higher neurotrophin concentrations. Analysis of the timing of cell death in the trigeminal ganglia of mouse embryos that are homozygous for null mutations in the TrkA, TrkB and TrkC genes which encode high affinity receptors for NGF, BDNF and NT3 respectively, show that there is an early peak of apoptosis in TrkB and TrkC knockouts which is consistent with the early survival response of trigeminal neurons to BDNF and NT3 in vitro. The elevated peak of apoptosis in TrkA knockouts occurs at the same development stages as in wild type embryos which is consistent with the later response of trigeminal neurons to NGF in vitro. Furthermore, there is a high level of expression of TrkC mRNA in early trigeminal neurons which accords with the early survival response of these neurons to NTS. It is also shown that subsets of trigeminal neurons discriminate between neurotrophins at very high concentrations during the period of cell death, indicating that neurotrophin responses can be far more highly specific than previously thought. Taken together, these results show that neurotrophin switching is a physiologically relevant phenomenon in certain populations of developing sensory neurons.