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Thesis (Ph. D.)--University of Texas at Austin, 2004. / Supervisor: R. Adron Harris. Vita. Includes bibliographical references.

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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.