by Chan Eliza. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1992. / Includes bibliographical references (leaves 90-95). / ACKNOWLEDGEMENTS --- p.i / ABSTRACT --- p.ii / Chapter CHAPTER 1 --- INTRODUCTION --- p.1 / Chapter CHAPTER 2 --- LITERATURE REVIEW / Chapter SECTION 1 --- Classification of cutaneous mechanoreceptors in the mammalian skin --- p.3 / Chapter 1.1 --- Criteria --- p.3 / Chapter 1.2 --- Slowly adapting type I mechanoreceptors --- p.3 / Chapter 1.3 --- Rapidly adapting mechanoreceptors --- p.6 / Chapter SECTION 2 --- Structural features of Merkel cells --- p.8 / Chapter 2.1 --- History --- p.8 / Chapter 2.2 --- General morphology of Merkel cells --- p.8 / Chapter 2.3 --- Electron microscopical description of the Merkel cell-neurite complexes --- p.10 / Chapter SECTION 3 --- Responsive features of Merkel cell as slowly adapting type I mechanoreceptors --- p.12 / Chapter 3.1 --- History --- p.12 / Chapter 3.2 --- Principles of the in-vivo and in-vitro techniques --- p.13 / Chapter 3.2.1 --- Location of Merkel cells --- p.13 / Chapter 3.2.2 --- Characteristic firing pattern of the slowly adapting type I mechanoreceptor --- p.14 / Chapter SECTION 4 --- Functional implications of the Merkel cell --- p.18 / Chapter 4.1 --- An analogy between Merkel cells and sensory hair cells of the auditory system --- p.18 / Chapter 4.1.1 --- Sensory hair cells of the acoustico-lateralis system --- p.18 / Chapter 4.1.2 --- Mechano-electrical activity of the Merkel cells --- p.21 / Chapter 4.2 --- Existence of dense-core vesicles --- p.21 / Chapter 4.2.1 --- Hypoxia reduced excitability of slowly adapting type I mechanoreceptors --- p.23 / Chapter 4.2.2 --- Calcium blockers affect the responsiveness of the slowly adapting type I mechanoreceptors --- p.24 / Chapter 4.3 --- Met-enkephalin as a putative neurotransmitter --- p.25 / Chapter SECTION 5 --- Met-enkephalin as an endogenous opioid peptide --- p.26 / Chapter 5.1 --- Synthesis and metabolic regulation of met-enkephalin --- p.26 / Chapter 5.2 --- The opioid receptors --- p.27 / Chapter 5.3 --- "Selective μ-, δ- and kappa- opioid receptor antagonists" --- p.28 / Chapter CHAPTER 3 --- METHODS / Chapter SECTION 1 --- In-vitro study --- p.30 / Chapter 1.1 --- Dissection --- p.30 / Chapter 1.2 --- Identification of a receptor and administration of chemicals --- p.34 / Chapter 1.2.1 --- Firing patterns of the type I and type II mechanoreceptors --- p.35 / Chapter 1.2.2 --- Interspike interval distributions (ISI) --- p.37 / Chapter 1.3 --- Administration of drugs --- p.39 / Chapter SECTION 2 --- Experimental setup --- p.39 / Chapter 2.1 --- Mechanical stimulation --- p.39 / Chapter 2.2 --- Recordings --- p.40 / Chapter 2.3 --- Data processing --- p.41 / Chapter SECTION 3 --- Preparation of drugs --- p.43 / Chapter 3.1 --- Mu- opioid receptor antagonists --- p.43 / Chapter 3.2 --- Delta- opioid receptor antagonist --- p.43 / Chapter 3.3 --- Kappa- opioid receptor antagonists --- p.44 / Chapter SECTION 4 --- Data analysis --- p.44 / Chapter 4.1 --- Comparison of data --- p.44 / Chapter 4.2 --- Statistics --- p.45 / Chapter CHAPTER 4 --- RESULTS / Chapter SECTION 1 --- Determination of an optimal stimulation force --- p.46 / Chapter SECTION 2 --- Effects of the mu- opioid receptor antagonists --- p.48 / Chapter 2.1 --- Naloxone --- p.48 / Chapter 2.2 --- β-FNA --- p.54 / Chapter 2.2.1 --- Slowly adapting type I mechanoreceptor --- p.54 / Chapter 2.2.2 --- Control study of vehicle --- p.54 / Chapter SECTION 3 --- Effects of the delta- opioid receptor antagonist ICI174864 --- p.58 / Chapter SECTION 4 --- Effects of the kappa- opioid receptor antagonists --- p.58 / Chapter 4.1 --- nor-BNI --- p.58 / Chapter 4.1.1 --- Slowly adapting type I mechanoreceptor --- p.58 / Chapter 4.1.2 --- Afferent nerve attached to the type I mechanoreceptor --- p.62 / Chapter 4.2 --- MR2266 --- p.65 / Chapter 4.2.1 --- Control study of vehicle --- p.67 / Chapter 4.2.2 --- Slowly adapting type I mechanoreceptor --- p.67 / Chapter 4.2.3 --- Afferent nerve attached to the type I mechanoreceptor --- p.73 / Chapter CHAPTER 5 --- DISCUSSION AND CONCLUSION / Chapter SECTION 1 --- Study of the slowly adapting type I mechanoreceptors using the in-vitro preparation --- p.80 / Chapter 1.1 --- Characteristic features of the slowly adapting type I mechanoreceptor --- p.81 / Chapter 1.2 --- Optimal force of stimulation --- p.82 / Chapter SECTION 2 --- Effects of the opioid receptor antagonists --- p.82 / Chapter 2.1 --- Lack of effects of the μ- and δ- opioid receptor antagonists --- p.83 / Chapter 2.2 --- The kappa- opioid receptor antagonists --- p.85 / Chapter 2.2.1 --- nor-BNI --- p.85 / Chapter 2.2.2 --- MR2266 --- p.86 / Chapter SECTION 3 --- Existence of opioidergic receptor sites in the Merkel cell-neurite complexes ？ --- p.87 / REFERENCES --- p.90

Thesis (Ph. D.)--Hong Kong University of Science and Technology, 2002. / On t.p. "A̳" is subsript. Includes bibliographical references (leaves 160-177). Also available in electronic version. Access restricted to campus users.

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Thesis (Ph. D.)--Rutgers University, 2008. / "Graduate Program in Neuroscience." Includes bibliographical references (p. 148-165).

Thesis (Ph.D.) - University of Queensland, 2003. / Includes bibliography.

The aim of this project was to determine the temporal and spatial pattern of expression of GDNF family receptors in the developing embryo, with particular emphasis on expression in the peripheral nervous system, and to investigate how expression of receptor mRNAs is regulated in developing neurons. It was hoped that the data obtained would prove useful in further characterizing the role that the GDNF family of neurotrophic factors play in embryonic development. Semi- quantitative PCR revealed that GFRα-1, GFRα-2, GFRα-4 and ret mRNAs are widely distributed with both complementary and overlapping, though distinct, patterns of expression in the chicken embryo during development. Different populations of PNS neurons display different levels of responsiveness to GDNF and NTN and their sensitivity to these factors change throughout development. Examination of receptor expression by quantitative RT-PCR revealed that neurons that are more sensitive to GDNF express higher levels of GFRα-1 mRNA than GFRα-2 mRNA, and neurons that are more sensitive to NTN express higher levels of GFRα-2 mRNA compared to GFRα-1 mRNA. However, developmental changes in responsiveness of a population of neurons to these factors are not consistently paralleled by changes in the relative levels of GFRα transcripts. Furthermore, all neuronal populations express relatively high levels of ret mRNA. These results indicate the responsiveness of PNS neurons to GDNF and NTN is in part governed by the relative levels of expression of their GPI-linked receptors. To determine how the expression of the GDNF family receptors is regulated, embryonic neurons were cultured under different experimental conditions. I found that GFRα-1, GFRα-2, GFRα-4 and ret mRNAs are not significantly regulated by GDNF and/or NTN. However, depolarizing levels of KC1 cause marked changes in the expression of GFRα mRNAs. The effects of KCl are inhibited by L-type Ca2+ channel antagonists, suggesting that they were mediated by elevation of intracellular free Ca2+. KCl treatment increases the response of neurons to GDNF and decreases their response to NTN. There is no marked effect of depolarization on ret mRNA expression.

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.

The main aim of this project was to determine the neurotrophic actions of glial cell line-derived neurotrophic factor (GDNF) and neurturin, two novel members of the transforming growth factor-beta superfamily of proteins, on neurons from the peripheral nervous system and to identify their receptors. It is found that GDNF promotes the survival of multiple populations of chicken sensory and autonomic neurons in culture throughout development. Whereas sympathetic, parasympathetic and propioceptive neurons become less responsive to GDNF with age, enteroceptive and sensory cutaneous neurons become more responsive to GDNF. GDNF mRNA is expressed in the tissues innervated by these neurons, and developmental changes in its expression in several tissues mirror the changing responses of the innervating neurons to GDNF. These results have changed the previous notion that GDNF is a highly specific neurotrophic factor for motoneurons and dopaminergic neurons. It is shown that neurturin, which is structurally related to GDNF, also promotes the in vitro survival of embryonic chicken sensory and autonomic neurons. Thus, GDNF and neurturin compose a novel subfamily of homologous neurotrophic factors with a similar pattern of activity. The cloning of chicken GDNF receptor-α (GDNFR-α) and a novel receptor termed neurturin receptor-α (NTNR-α) is reported. GDNFR-α and NTNR-α are homologous receptors linked to the membrane via a glycosyl- phosphatidylinositol linkage. It is shown that ectopic co-expression in neurons of GDNFR-α with RET (rearranged during transfection), a transmembrane receptor tyrosine kinase, confers a survival response to GDNF, but not neurturin, and that co-expression of NTNR-α with RET confers a survival response to neurturin, but not GDNF. GDNFR-α and NTNR-α mRNAs are widely expressed in the nervous system, including GDNF and neurturin responsive neurons, and in non-neuronal tissues. These findings indicate that GDNF and neurturin promote neuronal survival by signalling via similar multicomponent receptors that consist of a common transducing receptor tyrosine kinase and a member of a newly emerging family of glycosyl-phosphatidylinositol-linked receptors that confer ligand- specificity.