Functional analysis of the novel brain-specific receptor tyrosine kinase "Sky"

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Sky (also known as Tyro3 and Rse) (Ohashi, et al.1994) is a member of Axl/UFO receptor tyrosine kinase family, which has two immunoglobulin (Ig)-like repeats and two fibronectin type III (FN III) -like repeats in the extracellular domain. Recently, Gas6 has been identified as ligand for all members of Axl receptor tyrosine kinase family ; Axl, Sky and c-Mer with different affinity (in this order). However physiological function of Sky and Gas6 in the nervous system are poorly understood, despite its importance in the nervous system suggested by the structural feature and predominant expression of Sky in the brain. Here we show by RNAse protection assay (RPA) and/or by in situ hybridization analysis that sky and gas6 mRNAs were expressed in adult hippocampus from CA1 region to CA3 region and dentate gyrus.Furthermore this expression was regulated in a similar manner during development ; levels were low during embryonic stages, gradually increased during development and reaching its highest levels in the adult. Sky-but not Axl-immunoreactivity was observed in the pyramidal layr of adult hippocampus, suggesting the roles of Sky and Gas6 hippocampus during development and in the adult. Recombinant rat Gas6 attenuated hippocampal neuronal cell death caused by serum starvation in vitro, indicating that Gas6 is a novel neurotrophic factor for hippocampal neurons in vitro. Finally, gas6 showed regulated expression in the hippocampus after kainic acid stimulation and in the sciativ nerve after nerve transection. Taken together, these findings indicate the physiological importance of Gas6 and Sky receptor tyrosine kinase in both central and peripheral nervous systems.