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1.
Sci Adv ; 9(3): eade9459, 2023 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-36662852

RESUMO

Severe, early-onset photoreceptor (PR) degeneration associated with MERTK mutations is thought to result from failed phagocytosis by retinal pigment epithelium (RPE). Notwithstanding, the severity and onset of PR degeneration in mouse models of Mertk ablation are determined by the hypomorphic expression or the loss of the Mertk paralog Tyro3. Here, we find that loss of Mertk and reduced expression/loss of Tyro3 led to RPE inflammation even before eye-opening. Incipient RPE inflammation cascaded to involve microglia activation and PR degeneration with monocyte infiltration. Inhibition of RPE inflammation with the JAK1/2 inhibitor ruxolitinib mitigated PR degeneration in Mertk-/- mice. Neither inflammation nor severe, early-onset PR degeneration was observed in mice with defective phagocytosis alone. Thus, inflammation drives severe, early-onset PR degeneration-associated with Mertk loss of function.


Assuntos
Degeneração Retiniana , Retinose Pigmentar , Camundongos , Animais , c-Mer Tirosina Quinase/genética , c-Mer Tirosina Quinase/metabolismo , Epitélio Pigmentado da Retina/metabolismo , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Degeneração Retiniana/genética , Degeneração Retiniana/metabolismo , Retinose Pigmentar/genética , Retinose Pigmentar/metabolismo , Inflamação/genética , Inflamação/metabolismo
2.
Elife ; 112022 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-35969037

RESUMO

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 accounts for the absence of anti-tumor immunity. Collectively, our results indicate that context-dependent epistasis of independent modifier alleles determines Mertk KO traits.


Assuntos
Degeneração Retiniana , Alelos , Animais , Modelos Animais de Doenças , Camundongos , Camundongos Knockout , Fagocitose/genética , Fenótipo , Proteínas Proto-Oncogênicas/genética , Degeneração Retiniana/genética , Degeneração Retiniana/patologia , Pigmentos da Retina , c-Mer Tirosina Quinase/genética , c-Mer Tirosina Quinase/metabolismo
3.
Nat Commun ; 13(1): 7689, 2022 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-36509738

RESUMO

The fine equilibrium of bone homeostasis is maintained by bone-forming osteoblasts and bone-resorbing osteoclasts. Here, we show that TAM receptors MERTK and TYRO3 exert reciprocal effects in osteoblast biology: Osteoblast-targeted deletion of MERTK promotes increased bone mass in healthy mice and mice with cancer-induced bone loss, whereas knockout of TYRO3 in osteoblasts shows the opposite phenotype. Functionally, the interaction of MERTK with its ligand PROS1 negatively regulates osteoblast differentiation via inducing the VAV2-RHOA-ROCK axis leading to increased cell contractility and motility while TYRO3 antagonizes this effect. Consequently, pharmacologic MERTK blockade by the small molecule inhibitor R992 increases osteoblast numbers and bone formation in mice. Furthermore, R992 counteracts cancer-induced bone loss, reduces bone metastasis and prolongs survival in preclinical models of multiple myeloma, breast- and lung cancer. In summary, MERTK and TYRO3 represent potent regulators of bone homeostasis with cell-type specific functions and MERTK blockade represents an osteoanabolic therapy with implications in cancer and beyond.


Assuntos
Proteínas Proto-Oncogênicas , Receptores Proteína Tirosina Quinases , Camundongos , Animais , c-Mer Tirosina Quinase/genética , c-Mer Tirosina Quinase/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Homeostase , Proteínas de Transporte
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