Table 3. Abnormal phenotypes observed in mice after knocking out miRNAs representing multiple miRNA families.
For each miRNA family, its conservation is listed in parentheses, together with the number of murine genes that contribute to that family. The conservation categories are bilaterian (bilat., conserved since the bilaterian ancestor), vertebrate (vert., conserved among mammals and fish but emerged since the bilaterian ancestor), eutherian (euth., conserved among placental mammals but not to fish), and poorly conserved (p.c., not conserved among placental mammals). Each strain has 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 families (conservation, # of genes) | miRNA(s) removed | Phenotype |
|---|---|---|
| miR-1/206 (bilat. 3), miR-133 (bilat. 3) | miR-1-1 ~ miR-133a-2, miR-1-2 ~ miR-133a-1 | Early embryonic lethality, complete penetrance, due to severe heart malformations (Wystub et al., 2013) |
| miR-96 (bilat. 1), miR-183 (bilat. 1), miR-182 (vert. 1) | miR-183 ~ 96 ~ 182 | Retinal degeneration following progressive synaptic defects of photoreceptors; impaired balance (Lumayag et al., 2013); decreased corneal nerve density; increased neutrophil activity; decreased disease with Pseudomonas infection of the cornea (Muraleedharan et al., 2016) |
| miR-96 (bilat. 1), miR-183 (bilat. 1) | miR-183 ~ 96 | Defects in retinal cone development, progressive loss of photoreceptor fuction, retinal degeneration; impaired balance; impaired olfactory function (Xiang et al., 2017) |
| miR-193 (bilat. 2), miR-365 (bilat. 2) | miR-193b ~ 365-1 | Increased mammary stem/progenitor cells; accelerated differentiation of mammary epithelium during puberty and pregnancy (Yoo et al., 2014) |
| miR-25/32/92/363/367 (bilat. 7), miR- 17/20/93/106 (vert. 6), miR-18 (vert. 2), miR-19 (vert. 3) | miR-17 ~ 18 ~ 19a ~ 20a ~ 19b-1 ~ 92a-1 | Perinatal lethality, complete penetrance, due to lung and heart defects; vertebral homeotic transformations and other skeletal defects; reduced body weight; reduced pre-B cells (Ventura et al., 2008; Han et al., 2015); conditional deletion perturbs development and/or function in each of 18 different cell types |
| miR-25/32/92/363/367 (bilat. 7), miR-17/20/93/106 (vert. 6), miR-18 (vert. 2), miR-19 (vert. 3) | miR-17 ~ 18 ~ 19a ~ 20a ~ 19b-1 ~ 92a-1, miR-106b ~ 93 ~ 25 | Embryonic lethality, complete penetrance, at midgestation (Ventura et al., 2008) |
| miR-25/32/92/363/367 (bilat. 7), miR-17/20/93/106 (vert. 6) | miR-106b ~ 93 ~ 25 | Enhanced adiposity leading to insulin resistance (Cioffi et al., 2015); cardiac arrhythmia (Chiang et al., 2014) |
| miR-23 (vert. 2), miR-24 (vert. 2), miR-27 (vert. 2) | miR-23a ~ 27a ~ 24-2, miR-23b ~ 27b ~ 24-1 | Hypersensitive T cells; increased T helper cell responses and tissue pathology in an immune disease model (asthma) (Pua et al., 2016); decreased hematopoietic stem cells and progenitors; skewed hematopoiesis, with B cells produced at the expense of myeloid cells (Kurkewich et al., 2016; Kurkewich et al., 2017) |
| miR-200bc/429 (bilat. 3), miR-200a/141 (vert. 2) | miR-200c ~ 141 | Impaired enamel formation (Cao et al., 2013) |
| miR-200bc/429 (bilat. 3), miR-200a/141 (vert. 2) | miR-200b ~ 200a ~ 429 | Adipocyte-specific knockout causes increased obesity with high-fat diet (Tao et al., 2016) |
| miR-143 (vert. 1), miR-145 (vert. 1) | miR-143 ~ 145 | Arterial smooth muscle defects with perturbed actin stress fibers; increased lethality and less scarring in response to vascular injury (Elia et al., 2009; Xin et al., 2009); swelling of the kidney due to impaired ureter function (Medrano et al., 2014); reduced intraocular pressure (Li et al., 2017); altered pathology in several disease/injury models |
| miR-144 (vert. 1), miR-451 (vert. 1) | miR-144 ~ 451 | Increased incidence of spontaneous B lymphoma and acute myeloid leukemia in aged mice (Ding et al., 2017) |
| miR-216a (bilat. 1) miR-216b (vert. 1), miR-217 (vert. 1) | miR-216b ~ 216a ~ 217 | Embryonic lethality at about E9.5, complete penetrance (Azevedo-Pouly et al., 2017) |
| miR-199 (vert. 3), miR-214 (vert. 1) | miR-199a-2 ~ 214 | Neonatal and postnatal lethality, partial penetrance, smaller body size, skeletal abnormalities, partial paralysis (Watanabe et al., 2008) |
| miR-291a/294/302abd (vert. 5), 4 other less broadly conserved families | miR-290 ~ 291a ~ 292 ~ 291b ~ 293 ~ 294 ~ 295 | Embryonic lethality, partially penetrant; female sterility with ovarian failure due to defects in primordial germ cell migration (Medeiros et al., 2011); smaller placenta with defective maternal–fetal transport (Paikari et al., 2017) |
| miR-291a/294/302abd (vert. 5), miR-302c (vert. 1) | miR-302b ~ 302c ~ 302a ~ 302d | Late embryonic lethality, complete penetrance; failure of neural tube closure, with precocious neuronal differentiation and increased proliferation of neural progenitors; abnormal eye development (Parchem et al., 2015) |
| miR-291a/294/302abd (vert. 5), miR-302c (vert. 1), 4 other less broadly conserved families | miR-290 ~ 291a ~ 292 ~ 291b ~ 293 ~ 294 ~ 295, miR-302b ~ 302c ~ 302a ~ 302d | Early embryonic lethality, complete penetrance (Parchem et al., 2015) |
| miR-208 (vert. 2), miR-499 (vert. 1) | miR-208b, miR-499 | Reduced proportion of slow myofibers in skeletal muscle (van Rooij et al., 2009) |
| miR-15/16/195/322/497 (vert. 7), miR-503 (euth. 1) | miR-322 ~ 503 | Defects in mammary gland involution after weaning; increased body weight due to more white fat (Llobet-Navas et al., 2014); increased tumorigensis of breast cancer in sensitized background (Rodriguez-Barrueco et al., 2017); increased angiogenic response to inflammation (Lee et al., 2017) |
| miR-15/16/195/322/497 (vert. 7), miR-503 (euth. 1), miR-351 (p.c. 1) | miR-322 ~ 503 ~ 351 | Deletion in cartilage causes perinatal lethality, partial penetrance, due to tracheal defects (observed specifically in pure C57BL/6N genetic background) (Bluhm et al., 2017) |
| miR-431 (euth. 1), miR-433 (euth. 1), miR-127 (euth. 1), miR-434 (p.c. 1) | miR-431 ~ 433 ~ 127 ~ 434 | Note that the following phenotypes are observed only when inheriting deletion from maternal allele (part of paternally imprinted cluster expressed from only maternal allele). Either neonatal lethality or slower growth after weaning, depending on genetic background; enlarged placenta with defects (Sekita et al., 2008) |
| Cluster of 36 genes from 35 families; all but two of the 35 families have only a single murine gene (exceptions, miR-381/539 and miR-329/362); 27 families conserved among eutheria, the other 8 conserved less broadly | miR-379 ~ 411 ~ 299 ~ 380 ~ 1197 ~ 323 ~ 758 ~ 329 ~ 494 ~ 679 ~ 1193 ~ 666 ~ 543 ~ 495 ~ 667 ~ 376c ~ 376b ~ 376a ~ 300 ~ 381 ~ 487b ~ 539 ~ 544 ~ 382 ~ 134 ~ 668 ~ 485 ~ 154 ~ 496a ~ 377 ~ 541 ~ 409 ~ 412 ~ 369 ~ 410 ~ 3072 | Note that the following phenotypes are observed only when inheriting deletion from maternal allele (paternally imprinted cluster expressed from only maternal allele). Neonatal lethality, partial penetrance; transient postnatal growth retardation; postnatal metabolic defects, including inefficient mobilization of glycogen stores (Labialle et al., 2014); increased anxiety-related behavior in adult mice (Marty et al., 2016) |