verbatim): The experiments of this application are designed to assess the function of the three cell surface receptor tyrosine kinases of the Tyro 3 family. These proteins, designated Tyro 3, Ax1, and Mer, are expressed in a variety of differentiated cell types in the central and peripheral nervous systems, in the immune and hematopoietic systems, and in the endocrine and reproductive systems, where they are thought to receive extracellular signals that regulate trophic interactions and cellular homeostasis. These signals are conveyed by Gas6 and protein S, two polypeptide ligands that bind to, and thereby activate Tyro 3 family receptors. The studies proposed rely on a unique set of genetic reagents -- mutant mice that lack the function of each of the receptors, both singly and in combination. These mice, particularly those that carry mutations in more than one of the three receptor genes, display devastating major organ defects, neurological abnormalities, and physiological deficits as adults. They are infertile, blind, and prone to epileptiform seizures. Their immune systems are seriously compromised, their vasculature appears to be weakened, and their brains, livers, and reproductive organs undergo widespread cellular degeneration. Most remarkably, these phenomena appear to be truly degenerative as opposed to developmental: each of the affected tissues undergoes superficially normal embryonic and early postnatal development, and only then is the degeneration of cells and tissues observed. We will use a combination of genetic, biochemical, and immunohistochemical methods to understand the cellular basis of the degeneration observed in each of the affected tissues. We will determine what cells are degenerating and how they are degenerating, when degeneration begins and ends, what cells in the affected tissues express which and how many of the receptor genes that have been inactivated, whether the receptor-expressing cells are also those that degenerate, and what cells in the affected tissues express which ligands. Together, these studies will reveal the basics of cell-to-cell signaling through Tyro 3, Axl, and Mer -- three receptors of genuine biological importance.
