Table 2. Abnormal phenotypes observed in mice after knocking out one or more members of a broadly conserved miRNA family.
This table lists results for 36 of the 62 families that are conserved among mammals and fish but emerged since the bilaterian ancestor (Table S1). For two of the remaining 26 families, a knockout has been generated and reported to have no observed phenotype; these are the miR-30 family, for which two of the six members (miR-30d ~ miR-30b) have been simultaneously deleted (Park et al., 2012), and the miR-144 family, for which the one-and-only member was deleted (Rasmussen et al., 2010). Some strains have more than one miRNA gene disrupted; multiple miRNAs from a disrupted polycistronic locus are linked with a tilde (~), whereas those from distant loci are separated with a comma.
| miRNA family (# of genes) | miRNA(s) removed | Phenotype |
|---|---|---|
| miR-15/16/195/322/497 (7) | miR-15a ~ 16-1 | Increased proliferation of B cells; development of lymphoproliferative disorders (Klein et al., 2010); arrested maturation of natural killer cells (Sullivan et al., 2015); increased phagocytosis of macrophages; reduced mortality in bacterial sepsis models (Moon et al., 2014) |
| miR-15b ~ 16-2 | Development of B cell lymphoproliferative disorders (Lovat et al., 2015) | |
| miR-17/20/93/ 106 (6) | miR-17, miR-20a | Perinatal lethality, incomplete penetrance; vertebral homeotic transformations and other skeletal defects; reduced body weight; reduced pre-B cells (Han et al., 2015) |
| miR-18 (2) | miR-18a | Reduced body weight (Han et al., 2015) |
| miR-19 (3) | miR-19a, miR-19b-1 | Perinatal lethality, incomplete penetrance; reduced body weight; reduced tumorigenesis in sensitized background (Myc) (Han et al., 2015) |
| miR-21 (1) | miR-21 | Reduced growth and increased apoptosis of eosinophil progenitors (Lu et al., 2013b); altered macrophage polarization with more M2 macrophages and fewer M1 macrophages (Wang et al., 2015); increased bone mass with decreased bone resorption (Hu et al., 2017); altered pathology in > 20 disease/injury models |
| miR-23 (2) | miR-23a | Deletion in T cells causes reduced survival of activated T cells and increased susceptibility to bacterial infection (Listeria) (Zhang et al., 2016a) |
| miR-122 (1) | miR-122 | Development of fatty liver, hepatitis, fibrosis, and hepatocellular carcinoma (Hsu et al., 2012; Tsai et al., 2012); smaller hepatocytes with substantially fewer polyploid cells (Hsu et al., 2016); increased susceptibility to acetaminophen toxicity (Chowdhary et al., 2017) |
| miR-126 (1) | miR-126 | Embryonic lethality, incomplete penetrance, with hemorrhaging due to loss of vascular integrity and defects in endothelial cell proliferation, migration, and angiogenesis (Kuhnert et al., 2008; Wang et al., 2008); defects in innate immune response (Agudo et al., 2014); exacerbated atherosclerosis in sensitized background (Apoe) (Schober et al., 2014) |
| miR-128 (2) | miR-128-2 | Development of fatal epilepsy, complete penetrance, preceded by hyperactivity and increased exploration (Tan et al., 2013) |
| miR-130/301 (4) | miR-301a | Reduced pathology in models of colitis and colitis-associated cancer; reduced tumorigenesis of lung, thymus, and skin cancers in sensitized background (Kras) (Ma et al., 2015) |
| miR-132/212 (2) | miR-212 ~ 132 | Impaired memory formation and retention (Hernandez-Rapp et al., 2015; Hansen et al., 2016); reduced depth perception with impaired maturation of binocular cortical cells (Mazziotti et al., 2017); perturbed circadian regulation with reduced dendritic spines in neurons of suprachiasmatic nucleus (Kiessling et al., 2017; Mendoza-Viveros et al., 2017); perturbed cortical synaptic transmission and plasticity (Remenyi et al., 2013); increased endothelial vasodilatory function; increased angiogenic responses (Kumarswamy et al., 2014); altered survival, proliferation, and differentiation of hematopoietic stem cells (Mehta et al., 2015); altered pathology in six disease/injury models |
| miR-137 (1) | miR-137 | Early embryonic lethality, complete penetrance (Crowley et al., 2015) |
| miR-139 (1) | miR-139 | Increased pathology in models of colitis and colitis-associated cancer (Maoa et al., 2015; Zou et al., 2016) |
| miR-140 (1) | miR-140 | Dwarfism and craniofacial deformities, with premature differentiation of chondrocytes; osteoarthritis (Miyaki et al., 2010; Nakamura et al., 2011); increased Leydig cells in developing testes (Rakoczy et al., 2013) |
| miR-142 (1) | miR-142 | Reduced CD4+ dendritic cells (Mildner et al., 2013); decreased platelets due to impaired megakaryocyte maturation (Chapnik et al., 2014); reduced function of mast cells (Yamada et al., 2014); impaired T and B1B cell development and function with immunodeficiency (Kramer et al., 2015; Sun et al., 2015; Mildner et al., 2017); impaired erythropoiesis leading to anemia (Rivkin et al., 2017) |
| miR-143 (1) | miR-143 | Arterial smooth muscle defects with perturbed actin stress fibers; less scarring in response to vascular injury (Xin et al., 2009) |
| miR-145 (1) | miR-145 | Reduced vascular tone with reduced blood pressure; reduced heart mass; arterial smooth muscle defects with perturbed actin stress fibers; increased lethality and less scarring in response to vascular injury (Xin et al., 2009); reduced pathology in pulmonary disease model (fibrosis) (Yang et al., 2013) |
| miR-146 (2) | miR-146a | Hyperresponsive macrophages, exaggerated inflammatory response, and myeloid cell proliferation; eventual autoimmune disorders, exhaustion of hematopoietic stem cells, and hematopoietic neoplasms (Lu et al., 2010; Boldin et al., 2011; Zhao et al., 2013); altered pathology in five disease models |
| miR-146b | Enlarged spleens and increased myeloid cells, spontaneous intestinal inflammation, enhanced M1 macrophage polarization (Peng et al., 2016) | |
| miR-148/152 (3) | miR-148a | Elevated serum and hepatic cholesterol; accelerated carcinogenesis in chemically induced liver cancer (Cheng et al., 2017) |
| miR-150 (1) | miR-150 | Increased B1 cells and enhanced humoral immune response (Xiao et al., 2007); impaired maturation of natural killer T cells (Bezman et al., 2011; Zheng et al., 2012); impaired CD8+ T cell differentiation and function (Smith et al., 2015); reduced bone mass (Choi et al., 2015); altered pathology in eight disease models |
| miR-155 (1) | miR-155 | Impaired development and function of B cells, T cells, and dendritic cells (Rodriguez et al., 2007; Thai et al., 2007; Kohlhaas et al., 2009; Lu et al., 2009; O’Connell et al., 2010; Dunand-Sauthier et al., 2011); perturbed function of macrophages and mast cells (O’Connell et al., 2009; Qayum et al., 2016); altered pathology in > 60 disease/injury models |
| miR-181 (6) | miR-181a-1 ~181b-1, miR-181a-2 ~ 181b-2, miR-181c ~ 181d | Embryonic lethality, complete penetrance (Fragoso et al., 2012; Henao-Mejia et al., 2013) |
| miR-181a-1 ~ 181b-1, miR-181a-2 ~ 181b-2 | Postnatal lethality, incomplete penetrance; reduced body weight; defects in B and T cell development (Henao-Mejia et al., 2013) | |
| miR-181a-1 ~ 181b-1 | Defects in B and T cell development, loss of natural killer T cells (Fragoso et al., 2012; Henao-Mejia et al., 2013; Zietara et al., 2013); reduced leukemia in sensitized background (Notch1) (Fragoso et al., 2012) | |
| miR-182 (1) | miR-182 | Defective antibody response (Li et al., 2016); muscle loss; fast-to-slow fiber-type switching; impaired glucose metabolism (Zhang et al., 2016b); fewer circulating tumor cells and reduced metastasis in model of lung metastasis (Sachdeva et al., 2014) |
| miR-191 (1) | miR-191 | Deletion in T cells causes reduced survival of T cells (Lykken and Li, 2016) |
| miR-192/215 (2) | miR-192 | Reduced kidney pathology in diabetes model (Deshpande et al., 2013) |
| miR-196 (3) | miR-196a, miR-196a-2,miR-196b | Vertebral homeotic transformations, increased vertebral number (Wong et al., 2015) |
| miR-199 (3) | miR-199a-2 | Premature death, starting at 6 weeks; smaller body size; perturbed gait, body trembling, irregular breathing, and hypoactivity; smaller brain size with perturbed hippocampal and cortical neuron shape and density (Tsujimura et al., 2015) |
| miR-203 (1) | miR-203 | Thickened epidermis, enhanced tumorigenesis in chemically induced skin cancer (Riemondy et al., 2015) |
| miR-204/211 (2) | miR-204 | Improved glucose tolerance; reduced pathology in model of diabetes (Jo et al., 2018) |
| miR-211 | Retinal cone degeneration and impaired vision (Barbato et al., 2017) | |
| miR-205 (1) | miR-205 | Postnatal lethality, incomplete penetrance; fragile skin and impaired hair growth due to reduced neonatal expansion of progenitors and stem cells of hair follicles and skin (Farmer et al., 2013; Wang et al., 2013); no tear glands, 50% penetrance, or defective tear-gland development (Farmer et al., 2017); deletion in thymic epithelial cells causes of T cell defects (Hoover et al., 2016) |
| miR-208 (2) | miR-208a | Abnormal atrial cardiac conduction (Callis et al., 2009); reduced cardiac pathology in response to stress and in model of hypothyroidism (van Rooij et al., 2007) |
| miR-214 (1) | miR-214 | Increased pathology in heart disease model (Aurora et al., 2012) |
| miR-218 (2) | miR-218-1, miR-218-2 | Neonatal lethality, complete penetrance, due to lack of respiration; failure of many motor neurons to establish neuromuscular junctions; motor neuron hyperexcitability and degeneration (Amin et al., 2015) |
| miR-223 (1) | miR-223 | Perturbed development of myeloid lineages, with increased proliferation of progenitors and hyperactive neutrophils and macrophages; increased spontaneous and induced lung pathology (after endotoxin challenge); altered susceptibility to infection (Johnnidis et al., 2008; Zhuang et al., 2012; Lu et al., 2013a); increased serum cholesterol and triglycerides (Vickers et al., 2014); altered pathology in > 12 disease models. |
| miR-338 (1) | miR-338 | Heterozygous deletion causes disrupted synaptic transmission at auditory thalamocortical projections (Chun et al., 2017) |
| miR-451 (1) | miR-451 | Mild anemia and splenomegaly due to impaired erythroblast maturation (Patrick et al., 2010; Rasmussen et al., 2010) |