Identification of Gas6, a putative ligand for Sky and Axl receptor tyrosine kinases, as a novel neurotrophic factor for hippocampal neurons.

Sky (also known as "Tyro3" and "Rse") is a member of the Axl/Sky/Mer receptor tyrosine kinase family and has two immunoglobulin-like repeats and two fibronectin type III-like repeats in the extracellular domain. Gas6 is a ligand for all members of the Axl family, each of which (Axl, Sky, and c-Mer) has different affinities to Gas6. Physiological functions of Sky and Gas6 in the nervous system are not well understood, despite their importance, which is suggested by Sky structural features and its predominant expression in the brain. We found in the RNase protection assays that gas6 and sky mRNAs are expressed in the adult rat hippocampus and are similarly regulated during development. Expression levels were low during embryonic stages but gradually increased during development and reached the highest level in adulthood. Sky, but not Axl, immunoreactivity was observed in the adult hippocampus. Recombinant rat Gas6 attenuated hippocampal neuronal cell death that was caused by serum starvation in vitro, indicating that Gas6 is a novel neurotrophic factor for hippocampal neurons. Gas6 showed regulated expression in the sciatic nerve after nerve transection. Therefore, Sky and Gas6 have neurotrophic roles in the nervous system.