This research program aims to study the developmental regulation and functions of specific neuropeptide gene expression. Neuropeptides play important, though poorly understood, roles in the control of the body, its development and its behavior. They are expressed in highly stereotyped patterns of neurons that represent small subsets of the total cellular complement. While a large body of work has described neuropeptide expression and function in vitro, much remains to be understood about such processes in vivo. This research utilizes the advanced techniques available in Drosophila for molecular-genetic analyses. It will contribute to the study of health-related issues concerning both neuroscience and cancer: understanding what normally controls neuropeptide gene expression will help to address the incidence widespread, misregulated neuropeptide expression as occurs in abnormal cellular states like small cell lung cancers. The two long range goals of the work include (i) a better understanding of the mechanisms underlying neuropeptide gene expression by individual nerve cells. Clearly, events in vivo reflect complex responses to cellular interactions and to circulating factors that are difficult to emulate in vitro. The principle significance of proposed studies on the regulation of Drosophila FMRFamide gene expression is the use of in vivo techniques: we have identified key regions of a neuropeptide gene that are important for its proper expression and have found a genetic mutant that causes misregulated expression. We now propose to analyze the molecular mechanisms underlying these normal and abnormal patterns. This information will contribute to specific knowledge of neuropeptide gene regulation, and to a more comprehensive understanding of mechanisms underlying neuronal development. The second long range goal is (ii) an examination of the genetic defects that ensue as a consequence of mutations in the neuropeptide signaling pathways. Neuropeptides present a difficult problem for functional analysis because they contain a number of potential biologically active agents that may be working individually, or in concert. In this regard, genetics should prove a useful complement to these other forms of experimental analysis for the functional analysis of neuropeptides and their receptors. This research program aims to alter specific ligands and their receptors, define the consequences of such loss, and test resulting hypotheses by re-introduction of the normal sequences back into the animal.
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