UC San Diego

Tyro 3, Axl, and Mer (TAM), a unique family of receptor protein-tyrosine kinases (PTK) originally identified in this laboratory, are critical regulators of the immune, reproductive, and nervous systems. Many additional functions in other systems are yet to be fully revealed. It was the goal of this dissertation to elucidate the role of the TAM family in the retina. That a member of this family, Mer, plays an essential role in retinal function is indicated by the fact that inactivation of the gene leads to a dramatic degenerative phenotype in the retina. This phenotype provides an excellent mouse model for a debilitating disease called retinitis pigmentosa which causes blindness in humans. Understanding the biology of the TAM family in the retinal system will provide insight into the consequences of Mer mutations in humans. We undertook a series of histological, biochemical, functional, and genetic studies to reveal why the loss of Mer results in the death of photoreceptors, and how Mer might be acting in the retina. Our results define the retinal pigment epithelial (RPE) cell as the primary site of Mer action, and demonstrate that the ability of these cells to perform a critical phagocytic function in the retina is severely affected in the absence of Mer. They also reveal that Gas6, thought to be the sole ligand for Mer in the retina, is not essential for this specialized RPE phagocytosis. The action of Protein S, the likely functional ligand for Mer activation in the RPE, is described. Furthermore, expression of a second member of the TAM family, Tyro 3, at the same site as that of Mer in the RPE, highlights the fact that the TAM family signaling system underlying phagocytosis is more complex than initially suspected.These studies extend our knowledge of the role of TAM family function in retinal homeostasis. Not only do they describe specific expression patterns and interactions in the RPE, but they provide principles which may be applied more generally to other systems in which receptors of the TAM family subserve phagocytic function