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 Mertk KO mice. Mertk 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 Mertk alone is not sufficient for retinal degeneration. The widely used Mertk KO mouse carries multiple coincidental changes in its genome that affect the expression of a number of genes, including the Mertk paralog Tyro3. Retinal degeneration manifests only when the function of Tyro3 is concomitantly lost. Furthermore, Mertk 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 Mertk KO mice is not, however, phenocopied by the loss of Mertk alone. Neither Tyro3, nor macrophage phagocytosis by alternate genetic redundancy, account for the absence of anti-tumor immunity. Collectively, our results indicate that context-dependent epistasis of independent modifier alleles determines Mertk KO traits.
RNA-sequencing data sets and the processed data that support the findings of this study have been deposited to the Gene Expression Omnibus (GEO) under accession ID: GSE205070. All data generated or analyzed during this study are included in the manuscript and supporting files. Source data files have been provided for all figures included.
Tissue-specific modifier alleles determine Mertk loss-of-function traitsNCBI Gene Expression Omnibus,GSE205070.
- Carla V Rothlin
- Sourav Ghosh
- Carla V Rothlin
- Carla V Rothlin
- Silvia C Finnemann
- Marleen Ansems
- Lindsey D Hughes
- Lindsey D Hughes
- James Nevin
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: All experiments involving animals were performed in accordance with regulatory guidelines and standards set by the Institutional Animal Care and Use Committee (IACUC) protocol (#2021-11312) of Yale University.
- Florent Ginhoux, Agency for Science Technology and Research, Singapore
© 2022, Akalu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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