Tissue-specific modifier alleles determineMertkloss-of-function traits

Abstract

ABSTRACTKnockout (KO) mouse models play critical roles in elucidating biological processes behind disease-associated or disease-resistant traits. As a 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 withMertkKO. MERTK 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 phagocytosis of photoreceptor outer segments by retinal pigment epithelia. Similarly, enhanced anti-tumor immunity was inferred to result from the failure of macrophages to dispose cancer cell corpses, resulting in a pro-inflammatory tumor microenvironment. Here we report that the loss ofMertkalone is not sufficient for retinal degeneration. This trait only manifests when the function of the paralogTyro3is concomitantly lost. Additionally, the dramatic resistance against two syngeneic mouse tumor models observed inMertkKO cannot, at least entirely, be ascribed to the loss ofMertk. The widely usedMertkKO carries multiple coincidental changes in its genome that affect the expression of a number of genes, includingTyro3. Nonetheless, neitherTyro3, nor macrophage phagocytosis by alternate genetic redundancy, accounts for the absence of anti-tumor immunity in two independentMertkKOs. Collectively, our results indicate that context-dependent epistasis of independent modifier alleles determineMertkKO traits.