The mechanisms involved in cell fate decisions and axon guidance during the development of the of the nervous system are still poorly understood. The study of these mechanisms in animal systems may provide information relevant to the understanding of fetal and postnatal development of the human nervous system. The segmental ganglia of the embryonic insect central nervous system (CNS) provide a useful system in which to study these processes, because they contain a relatively small number of neurons that make genetically defined pathway choices. The basic architecture of these ganglia is conserved between species with large neurons suitable for cell biology studies, such as the grasshopper Schistocerca, and species with well-developed genetics, such as the fruit fly Drosophila melanogaster. The growth cones of insect CNS neurons make stereotyped pathway choices to reach their targets. The initial direction of growth cone extension is probably determined by transcriptional regulators that give the cell its unique identify. Subsequent pathway choices may be controlled by cell recognition molecules that are differentially expressed on subsets of CNS axons and cell bodies. These recognition molecules may transmit information back to the cell nucleus via signal transduction pathways and thereby modify the expression of regulatory genes. Genetic evidence suggests that signal transduction via control of tyrosine phosphorylation is an important element in cell fate and axon guidance decisions. One set of molecules that re likely to be important components of these signaling pathways are four receptor-linked protein tyrosine phosphatases (R-PTPs) that are selectively expressed on CNS axons in the Drosophila embryo. These R-PTPs have extracellular domaines like those of cell adhesion molecules, and are thus good candidates for molecules that directly couple cell recognition events to signal transduction pathways within the cell. This proposal describes experiments designed to elucidate the functions of axonal R-PTPs during insect CNS development. These R-PTPs may have redundant functions during embryonic development, because mutations in two R-PTP genes do not cause visible embryonic CNS phenotypes. A mutation in a third R-PTP gene has been identified, and its embryonic CNS phenotype will be examined. In addition, two R-PTPs are expressed on distinct subsets of neuronal processes in the larval optic lobes, suggesting that they may have unique functions during optic lobe development. These functions will be explored by examining the pattern of photoreceptor synapses in the optic lobes of mutant files. A putative downstream signaling molecule for one R-PTP has been identified, and its role in PTP signaling will be explored. Ligands that interact with the extracellular domains of the R-PTPs will be identified using molecular biological or biochemical techniques. To explore the mechanisms involved in development of the embryonic CNS, a system for studying cell fate decisions in grasshopper embryo cultures will be adapted to the study of the control of axon guidance by transcription factors. It will then be used to examine in detail the functions of the R-PTPs within several neuroblast lineages.
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