Vasoactive intestinal peptide (VIP) and the related neuropeptide pituitary adenylate cyclase activating peptide (PACAP) are potent regulators of neuroblast proliferation and survival in vitro. Administration of a VIP antagonist to pregnant mice produced a microcephaly condition in offspring, providing a new model for a human disease that is nearly always associated with mental retardation. In addition, VIP has been found to be highly upregulated in nerve injury models, and PACAP has been found to reduce the degree of cell death in the hippocampus following experimental forebrain ischemia. Thus, the VIP/PACAP ligand/receptor system may be important in CNS morphogenesis and injury. With respect to development, the current model contends that VIP is derived transplacentally from the mother, and thereby acts as a global regulator of embryonic CNS growth. However, key data from this laboratory indicate that the VIP gene is expressed in the mouse hindbrain as early as embryonic day 11, suggesting that the peptides are derived from the embryo and act in local domains (rather than globally) to regulate CNS development. In this proposal, the temporal and spatial expression patterns of VIP and PACAP, and their receptors during normal development will be determined using in situ hybridization and immunohistochemistry. The phenotype of potential target cell types will be identified by colocalizing receptors with markers for various developing neural lineages. It will also be determined if the VIP/PACAP ligand/receptor system is upregulated in an injury model. Based on the patterns of expression of peptide and receptor during development and after injury, in vitro model will be established to study the growth- or injury- related actions of these peptides on relevant cell populations Signal transduction pathways leading to these actions will be examined using pharmacological, biochemical, an molecular approaches. The results are expected to provide important mechanistic information on the role of peptides such as VIP and PACAP in normal and abnormal CNS development and after injury to the developing brain.
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