Tissue-specific modifier alleles determine Mertk loss-of-function traits

Abstract

Knockout (KO) mouse models play critical roles in elucidating biological processes behind disease-associated or disease-resistant traits. As a presumed consequence of gene KO, mice display certain phenotypes. Based on insight into the molecular role of said gene in a biological process, it is inferred that the particular biological process causally underlies the trait. This approach has been crucial towards understanding the basis of pathological and/or advantageous traits associated with <i>Mertk</i> KO mice. <i>Mertk</i> KO mice suffer from severe, early-onset retinal degeneration. MERTK, expressed in retinal pigment epithelia, is a receptor tyrosine kinase with a critical role in phagocytosis of apoptotic cells or cellular debris. Therefore, early-onset, severe retinal degeneration was described to be a direct consequence of failed MERTK-mediated phagocytosis of photoreceptor outer segments by retinal pigment epithelia. Here, we report that the loss of <i>Mertk</i> alone is not sufficient for retinal degeneration. The widely used <i>Mertk</i> KO mouse carries multiple coincidental changes in its genome that affect the expression of a number of genes, including the <i>Mertk</i> paralog <i>Tyro3</i>. Retinal degeneration manifests only when the function of <i>Tyro3</i> is concomitantly lost. Furthermore, <i>Mertk</i> KO mice display improved anti-tumor immunity. MERTK is expressed in macrophages. Therefore, enhanced anti-tumor immunity was inferred to result from the failure of macrophages to dispose of cancer cell corpses, resulting in a pro-inflammatory tumor microenvironment. The resistance against two syngeneic mouse tumor models observed in <i>Mertk</i> KO mice is not, however, phenocopied by the loss of <i>Mertk</i> alone. Neither <i>Tyro3</i> nor macrophage phagocytosis by alternate genetic redundancy accounts for the absence of anti-tumor immunity. Collectively, our results indicate that context-dependent epistasis of independent modifier alleles determines <i>Mertk</i> KO traits.