Table 1.
Germline overexpression and knockout models to evaluate in vivo miRNA functions
| Gene product | Expression in the study | Observed phenotypes | Refs |
|---|---|---|---|
| Oncogenes | |||
| miR-155 | Overexpressed in the B cell lineage | Late-onset B cell malignancy | 11 |
| Overexpressed in mature B cells | Increased fraction of germinal centre B cells | 14 | |
| Deleted in B cells | Reduction in the number of germinal centre B cells | 14 | |
| Ubiquitously deleted | Lung airway remodelling; enteric inflammation; impaired protective immunity owing to diminished B and T cell responses and impaired dendritic cell integrity | 13 | |
| Ubiquitously deleted | Loss of antigen- and tissue-specific inflammation | 12 | |
| miR-21 | Overexpressed in nestin-expressing cells | Pre-B-cell lymphoma | 21 |
| Ubiquitously overexpressed | No phenotype alone; potentiated KrasG12D-induced lung tumorigenesis | 19 | |
| Ubiquitously deleted | Attenuated KrasG12D-induced lung tumourigenesis | 19 | |
| Ubiquitously deleted | Reduction in DMBA–TPA-induced skin papillomas | 20 | |
| miR-29‡ | Overexpressed in immature and mature B cells | Indolent B-CLL | 59 |
| miR-17~92 | Overexpressed in lymphocytes | Lymphoproliferative disease and autoimmunity | 24 |
| Ubiquitously deleted | Post-embryonic premature death, lung hypoplasia and ventricular septal defect; inhibited pro-B to pre-B transition; in combination with miR-106b~25 deletion, led to death at midgestation | 23 | |
| miR-106a~363§ | Ubiquitously deleted | No phenotype | 23 |
| miR-106b~25§ | Ubiquitously deleted | No phenotype alone; death at midgestation when in combination with miR-17~92 deletion | 23 |
| Overexpressed in prostate epithelium (in combination with its host gene, MCM7) | Prostatic intraepithelial neoplasia | 31 | |
| LIN28 | Overexpressed | Enhanced growth and delayed puberty | 60 |
| Tumour suppressors | |||
| miR-15~16 | Point mutation 3' to the stem-loop structure of precursor (pre)-mir-16-1 | Autoimmune and B cell lymphoproliferative disease; B-CLL | 36, 37 |
| Deletion of 13q14 | Indolent B cell-autonomous, clonal lymphoproliferative disorders (monoclonal B cell lymphocytosis, CLL and non-Hodgkin lymphoma); disorders slightly more aggressive than mir-15a- and mir-16-1-null animals | 38 | |
| Deletion of mir-15a~16-1 | Indolent B cell-autonomous, clonal lymphoproliferative disorders (monoclonal B cell lymphocytosis, CLL and non-Hodgkin lymphoma) | 38 | |
| miR-146a‖ | Ubiquitously deleted | Myeloproliferation and haematolymphoid tumours (myeloid sarcomas and lymphomas); autoimmune disorders (splenomegaly, lymphadenopathy, multi-organ inflammation) | 45, 47 |
| DICER | Conditionally deleted in lung | Enhanced lung tumour development in KrasLSL–G12D mice (KrasLSL–G12D;Dicer1+/− and KrasLSL−G12D;Dicer1−/−); reduced survival of KrasLSL–G12D;Dicer1+/− mice when transgenes were induced in the lung | 64,160 |
| Conditionally deleted in lung or muscle | Haploinsufficient tumour suppressor; decreased survival in KrasLSL–G12D; Trp53fl/fl;Dicer1+/− (relative to Dicer1+/+ or Dicer1−/− triple transgenics) | 64 | |
| Conditionally deleted in retinoblasts | Haploinsufficient tumour suppressor in a retinoblastoma-sensitized background | 65 |
‡
Additional data support a role for miR-29a as a tumour suppressor.
§
Paralogue of miR17~92.
‖
In vitro data support an alternative role for miR-146a as an oncogene. B-CLL, B cell chronic lymphocytic leukaemia; DMBA, 7,12-dimethylbenz(a)anthracene; MCM7, mini-chromosome maintenance protein 7; miRNA, microRNA; TPA, 12-O-tetradecanoylphorbol-13-acetate.