Tissue-specific modifier alleles determine Mertk loss-of-function traits
- Yale University, United States
- Celldex Therapeutics, United States
- Fordham University, United States
- Columbia University, United States
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 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.
Data availability
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.
Article and author information
Author details
Silvia C Finnemann
Funding
National Institutes of Health (R01CA212376)
- Carla V Rothlin
- Sourav Ghosh
Howard Hughes Medical Institute
- Carla V Rothlin
Yale Cancer Center (YSPORE Career Development Award DRP27)
- Carla V Rothlin
Fordham University (Kim B. and Stephen E. Bepler Professorship in Biology)
- Silvia C Finnemann
Dutch Cancer Society (BUIT 2012-5347)
- Marleen Ansems
National Science Foundation (DGE-1122492)
- Lindsey D Hughes
Yale University (Richard K. Gershon Fellowship)
- Lindsey D Hughes
National Cancer Institute (2T32CA193200-06)
- James Nevin
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
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.
Reviewing Editor
- Florent Ginhoux, Agency for Science Technology and Research, Singapore
Version history
- Preprint posted: May 23, 2022 (view preprint)
- Received: May 24, 2022
- Accepted: August 13, 2022
- Accepted Manuscript published: August 15, 2022 (version 1)
- Version of Record published: August 31, 2022 (version 2)
Copyright
© 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.
Metrics
-
- 1,418
- Page views
-
- 291
- Downloads
-
- 11
- Citations
Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Tissue-specific modifier alleles determine Mertk loss-of-function traits
eLife 11:e80530.
https://doi.org/10.7554/eLife.80530
Further reading
-
- Cell Biology
- Immunology and Inflammation
Dendritic cells (DCs), the key antigen-presenting cells, are primary regulators of immune responses. Transcriptional regulation of DC development had been one of the major research interests in DC biology, however, the epigenetic regulatory mechanisms during DC development remains unclear. Here, we report that Histone deacetylase 3 (Hdac3), an important epigenetic regulator, is highly expressed in pDCs, and its deficiency profoundly impaired the development of pDCs. Significant disturbance of homeostasis of hematopoietic progenitors was also observed in HDAC3-deficient mice, manifested by altered cell numbers of these progenitors and defective differentiation potentials for pDCs. Using the in vitro Flt3L supplemented DC culture system, we further demonstrated that HDAC3 was required for the differentiation of pDCs from progenitors at all developmental stages. Mechanistically, HDAC3 deficiency resulted in enhanced expression of cDC1-associated genes, owing to markedly elevated H3K27 acetylation (H3K27ac) at these gene sites in BM pDCs. In contrast, the expression of pDC-associated genes was significantly downregulated, leading to defective pDC differentiation.
-
- Computational and Systems Biology
- Immunology and Inflammation
T cells are required to clear infection, and T cell motion plays a role in how quickly a T cell finds its target, from initial naive T cell activation by a dendritic cell to interaction with target cells in infected tissue. To better understand how different tissue environments affect T cell motility, we compared multiple features of T cell motion including speed, persistence, turning angle, directionality, and confinement of T cells moving in multiple murine tissues using microscopy. We quantitatively analyzed naive T cell motility within the lymph node and compared motility parameters with activated CD8 T cells moving within the villi of small intestine and lung under different activation conditions. Our motility analysis found that while the speeds and the overall displacement of T cells vary within all tissues analyzed, T cells in all tissues tended to persist at the same speed. Interestingly, we found that T cells in the lung show a marked population of T cells turning at close to 180o, while T cells in lymph nodes and villi do not exhibit this “reversing” movement. T cells in the lung also showed significantly decreased meandering ratios and increased confinement compared to T cells in lymph nodes and villi. These differences in motility patterns led to a decrease in the total volume scanned by T cells in lung compared to T cells in lymph node and villi. These results suggest that the tissue environment in which T cells move can impact the type of motility and ultimately, the efficiency of T cell search for target cells within specialized tissues such as the lung.
