Cell interactions are crucial to the establishment of order during development, for sensory perception, behavioral responses and homeostasis. Aberrant cellular communication has been largely studied in mammals in situations where it leads to inappropriate cell growth, contributing to neoplasia, or in context of genetically-inherited disease. In invertebrates, such as the fruitfly, Drosophila, it has been possible to use sophisticated genetic and molecular techniques to study mechanisms of cell communication and their developmental roles. One of the major pathways for communication between cells involves the stimulation of the synthesis of cyclic AMP (cAMP) in response to a specific extracellular signal. An intracellular cAMP signal is generally relayed by activation of cAMP-dependent protein kinase (PKA), which phosphorylates specific target proteins to alter their activity. The general objective of our research is to define the biological roles of PKA in Drosophila. We have found the PKA has several important behavioral and developmental roles in Drosophila but this research proposal concentrates on a single developmental function, the participation of PKA in the Hedgehog signal transduction pathway. Hedgehog is a secreted protein that was first discovered in Drosophila but which has close homologs in vertebrates. In Drosophila and in vertebrates Hedgehog proteins function in early development in many different tissues to direct the fates of large groups of cells according to their position. In mammals, aberrant Hedgehog signaling can result in extreme craniofacial defects (cyclopia), limb deformities, defects in ribs, spinal column and motor neuron formation or a propensity for basal cell carcinomas. Remarkably, many features of Hh signaling appear to be conserved between Drosophila and vertebrates, including the participation of PKA.
We aim to determine exactly how PKA acts to allow transduction of a Hh signal by identifying crucial PKA substrates, detailing the effects of PKA and Hh on a transcription factor (called Cubitus interruptus ) that mediate responses to Hedgehog and determining the outcome of simultaneous alteration of the activities of PKA and other putative Hedgehog signal transduction molecules. In this way we aim to understand a highly conserved role of PKA that governs development and cell growth in a multitude of organisms from flies to man.
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