JHIBRG:Abstract Mar 6 2008

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Loss of uPAR leads to abnormal hippocampal formation

The hippocampus is an integral brain structure involved in memory and cognition. Abnormal hippocampal formation causes neurological disorders such as memory deficits, schizophrenia, and epilepsy. The hippocampus is composed of several cell fields including CA3, CA1, and the dentate gyrus (DG). These structures form sequentially: the CA3 forms first, next the CA1 and finally DG. Formation of the granule cell layer (GCL) of DG starts during late embryonic development and continues into early postnatal stages. Neuroprogenitor cells in the inner most layer of the GCL continually generate neurons and maintain the granule cell layer through adulthood. Cell migration during hippocampal formation is under the control of site and time-specific expressing guidance molecules. One family of molecules expressed in the hippocampus is the plasminogen activators, tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA) and their receptors, including urokinase plasminogen activator receptor (uPAR). The uPAR can regulate cell proliferation, migration, differentiation, and survival, with binding partners such as uPA, integrin and growth factors. Its ligand, uPA, activates hepatocyte growth factor/scatter factor (HGF/SF). Loss of uPAR leads to a reduction of HGF/SF. Birthdating experiments in uPAR-/- mice demonstrate abnormal numbers and distribution of cells in the GCL as compared to wildtype mice. Interestingly, we found that fewer BrdU+ cells survived in the GCL of postnatal uPAR-/- mice as compared to wildtype mice. This data suggests that uPAR regulates cell migration and survival during hippocampal development.