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dc.contributor.authorSpöri, Bodo Karim Grischaen
dc.date.accessioned2018-05-14T10:16:26Z
dc.date.available2018-05-14T10:16:26Z
dc.date.issued2005en
dc.identifier.urihttp://hdl.handle.net/1842/30007
dc.description.abstracten
dc.description.abstract1. 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.en
dc.description.abstract2. 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.en
dc.description.abstract3. 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.en
dc.description.abstract4. 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.en
dc.description.abstractOverall, 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.en
dc.publisherThe University of Edinburghen
dc.relation.ispartofAnnexe Thesis Digitisation Project 2018 Block 18en
dc.relation.isreferencedbyAlready catalogueden
dc.titleInteraction between neurons, glia and target field cells in regulating the survival of cranial sensory neuronsen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen


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