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One important aspect of neural development is the differentiation of neurotransmitter phenotypes in developing neurons. The studies described in this dissertation explore mechanisms of transmitter differentiation using catecholaminergic (CA) phenotypic expression in sensory neurons as a model system. The results show that both environmental factors as well as intrinsic neuronal properties play key roles in regulating sensory CA phenotypic expression. Specifically, ganglionic non-neuronal cells (NNC) inhibit expression of the CA-biosynthetic enzyme tyrosine hydroxylase (TH) in cultured sensory neurons. The effect of NNC is partially mediated by a NNC-derived cytokine, Leukemia Inhibitory Factor (LIF). The detection of LIF and LIF receptor (LIFR) mRNAs in vivo suggests that LIF may be one factor that modulates CA potential in sensory neurons in vivo. In contrast to the inhibitory effect of LIF, depolarizing conditions up-regulate TH expression in cultured embryonic and newborn sensory neurons. These results raise the possibility that membrane depolarization during this critical period of development plays a role in stimulating CA differentiation in subsets of sensory neurons. Moreover, the effects of depolarization and LIF are antagonistic, suggesting that mature levels of CA expre ssion are regulated by a balance of positive and negative regulatory signals. Regulation of intrinsic neuronal properties, such as responsiveness to environmental influences, could be another general mechanism of neurotransmitter regulation. For example, nodose ganglion (NG) neurons lose their LIF responsiveness between embryonic and newborn stages, coincident with the development of a CA phenotype in a subset of NG neurons in vivo. This result raises the possibility that modulation of LIF responsiveness may contribute to stable, phenotypic TH expression in a subset of nodose neurons during late fetal development. To examine whether LIF inhibits sensory TH expression in vivo, I compared sensory TH expression in LIFR and LIF knockout mice with wildtype mice. TH cell numbers appeared unchanged in LIFR and LIF knockout mice compared to controls, indicating that the LIF system is dispensable for the normal patterning of TH expression in sensory neurons in vivo. These data suggest either (1) the loss of LIF function can be compensated for by other TH inhibitory factor(s), or (2) LIF may only be involved under culture conditions. In conclusion, my data indicate that spatial restriction of CA phenotypic expression in subsets of adult sensory neurons arises through modulation, by positive and negative extrinsic regulatory factors, of a widespread CA potential, as well as from the regulation of intrinsic neuronal responses to these environmental factors during development |
