1. AIMS: 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 in trigeminal neurons shortly after axons reach their targets
and NGF expression begins with the arrival of the earliest axons. This thesis was aimed at
investigating interactions between neurons and targets using the trigeminal ganglion and its
maxillary target field. Specifically, it assessed a. whether the induction and subsequent
developmental changes in trkA mRNA seen in the ganglion in vivo are intrinsically regulated
or dependent upon extrinsic signals, and whether N regulation ofNGF expression in the target
field is influenced by the innervating ganglion. Further, it was aimed at c. assessing the
importance of the trkA, trkB (BDNF-receptor) and full-length and truncated p75 neurotrophin
receptors in promoting survival in the developing trigeminal ganglion, and d. determining the
role of non target-related survival-mechanisms by Schwann cell precursors on trigeminal
ganglion neurons and other cranial sensory ganglia, namely the nodose, dorsal root and
superior cervical ganglia.2. METHODOLOGY: a. and b. Ganglion-target interactions and their effect on trkA and NGF
expression were assessed using cultures of trigeminal ganglia and its target fields alone or in
combination. Complementary approaches used knockout mice that increased or decreased the
neuronal population in the trigeminal ganglion in vivo. c. The role of the neurotrophin
receptors trkA, trkB and p75 in trigeminal neuron survival was assessed using knockout mice,
including double knockout mice for trkA and trkB. d. The role of Schwann cell precursors in
the survival of different populations of cranial sensory neurons was assessed using ErbB3
knockouts, which lack these cells.3. MAIN FINDINGS: a. Upregulation of trkA mRNA expression in the trigeminal ganglion
appears to follow an intrinsic programme, with in vitro expression levels mimicking levels in
vivo. However, extrinsic signals from the target-fields have a negative effect on trkA
expression in vitro, b. Early target field NGF mRNA expression was positively influenced by
ganglion innervation in vitro, and was significantly lower in the early target fields of embryos
lacking trigeminal neurons early in development in vivo. c. Double trkA/trkB knockouts
displayed neuronal death in the trigeminal ganglion, in a pattern suggesting that during certain
phases in development there are subsets of neurons, which can survive with either one or the
other receptor, whereas at other developmental stages both receptors are required. Neuronal
losses in different p75 mutant embryos suggest a survival-promoting effect of p75 early in
embryonic development, with truncated p75 having a role earlier in development than fulllength p75. d. Neuronal deficiencies in ErbB3-t- embryos support the idea that populations of
cranial sensory neurons differ in their survival-requirement for Schwann cell precursors early
in development, with early trigeminal and dorsal root neurons being more dependent on this
support than early nodose neurons.4. SYNTHESIS AND CONCLUSIONS: a. and b. The results suggest that in addition to intrinsic
mechanisms of regulation, trkA and NGF expression are subject to complex reciprocal
interactions between the trigeminal ganglion and its target fields early in development. The
control of survival of neurons during development may thus involve more than the restricted
supply of survival factor from the target field, c, Sequential dependence of sensory neurons on
one or more survival factor probably serves to increase survival to maximize the 'choice' of
the target field during naturally occurring cell death, and to establish heterogeneity in the
ganglion, d. Differences in the sensitivity of cranial sensory neurons to trophic support by
Schwann cell precursors during early development are presumably related to the distance
different populations grow to their target fields. Thus, in addition to survival provided by the
target field, neurons appear to depend on survival signals from surrounding cells between the
ganglion and the target field.Overall, these data support modifications to the way we should think about the way target
derived signals regulate the survival of peripheral neurons. Rather than being a passive receipt
of a restricted supply of NGF from the target field, it appears that complex target-ganglion
interactions are involved, as well as input from other neurotrophic factors, either separately or
in synergy with NGF, and input from non-target cells, such as Schwann cell precursors
