Species: C. elegans
Mutation name: None
type: null mutation
fertility: infertile - ovarian defect
Comment: Knight SW, et al reported a role for the RNase III enzyme DCR-1 in RNA interference and germ line development in Caenorhabditis elegans. An early event in RNA interference (RNAi) is the cleavage of the initiating double-stranded RNA (dsRNA) to short pieces, 21 to 23 nucleotides in length. The authors we describe a null mutation in dicer-1 (dcr-1), a gene proposed to encode the enzyme that generates these short RNAs and found find that dcr-1(-/-) animals have defects in RNAi under some, but not all, conditions. Mutant animals have germ line defects that lead to sterility, suggesting that cleavage of dsRNA to short pieces is a requisite event in normal development.

Species: mouse
Mutation name: None
type: null mutation
fertility: infertile - ovarian defect
Comment: Impaired microRNA processing causes corpus luteum insufficiency and infertility in mice. Otsuka M et al. The microRNA (miRNA) processing enzyme Dicer1 is required for zygotic and embryonic development, but the early embryonic lethality of Dicer1 null alleles in mice has limited our ability to address the role of Dicer1 in normal mouse growth and development. To address this question, we used a mouse mutant with a hypomorphic Dicer1 allele (Dicer(d/d)) and found that Dicer1 deficiency resulted in female infertility. This defect in female Dicer(d/d) mice was caused by corpus luteum (CL) insufficiency and resulted, at least in part, from the impaired growth of new capillary vessels in the ovary. We found that the impaired CL angiogenesis in Dicer(d/d) mice was associated with a lack of miR17-5p and let7b, 2 miRNAs that participate in angiogenesis by regulating the expression of the antiangiogenic factor tissue inhibitor of metalloproteinase 1. Furthermore, injection of miR17-5p and let7b into the ovaries of Dicer(d/d) mice partially normalized tissue inhibitor of metalloproteinase 1 expression and CL angiogenesis. Our data indicate that the development and function of the ovarian CL is a physiological process that appears to be regulated by miRNAs and requires Dicer1 function.

Species: mouse
Mutation name: None
type: null mutation
fertility: subfertile
Comment: Deletion of Dicer in somatic cells of the female reproductive tract causes sterility. Nagaraja AK et al. Dicer is an evolutionarily conserved RNase III that is necessary for microRNA (miRNA) processing and the synthesis of small interfering RNAs from long double-stranded RNA. While it has been shown that Dicer plays important roles in the mammalian germline and early embryogenesis, the functions of Dicer-dependent pathways in the somatic cells of the female reproductive tract are unknown. Using a transgenic line in which Cre is driven by the anti-M?an hormone receptor type 2 promoter, we conditionally inactivated Dicer1 in the mesenchyme of the developing M?an ducts and postnatally in ovarian granulosa cells and mesenchyme-derived cells of the oviducts and uterus. Deletion of Dicer in these cell types results in female sterility and multiple reproductive defects including decreased ovulation rates, compromised oocyte and embryo integrity, prominent bilateral paratubal (oviductal) cysts, and shorter uterine horns. The paratubal cysts act as a reservoir for spermatozoa and oocytes, and prevent embryos from transiting the oviductal isthmus and passing the uterotubal junction to enter the uterus for implantation. Deep sequencing of small RNAs in oviduct revealed downregulation of specific miRNAs in Dicer conditional knockout females compared to wild type. The majority of these differentially expressed miRNAs are predicted to regulate genes important for M?an duct differentiation and mesenchyme-derived structures, and several of these putative target genes were significantly upregulated upon conditional deletion of Dicer1. Thus, our findings reveal diverse and critical roles for Dicer and its miRNA products in the development and function of the female reproductive tract.

Species: mouse
Mutation name: None
type: null mutation
fertility: infertile - ovarian defect
Comment: Dicer1 is essential for female fertility and normal development of the female reproductive system. Hong X et al. The RNAse III endonuclease, Dicer1, is essential for the synthesis of the 19-25 nucleotide non-coding RNAs known as microRNAs (miRNA). These miRNAs associate with the RNA-induced silencing complex to regulate gene expression post-transcriptionally by base pairing with 3'untranslated-regions of complementary messenger RNA targets. While it is established that miRNAs are expressed in the reproductive tract their functional role and effect on reproductive disease remains unknown. The studies herein establish for the first time the reproductive phenotype of mice with loxP insertions in the Dicer1 gene (Dicer1(fl/fl)) when crossed with mice expressing Cre-recombinase driven by the anti-Mullerian hormone receptor 2 promoter (Amhr2(Cre/+)). Adult female Dicer1(fl/fl);Amhr2(Cre/+) mice displayed normal mating behavior, but failed to produce offspring when exposed to fertile males during a 5-month breeding trial. Morphological and histological assessments of the reproductive tracts of immature and adult mice indicated that the uterus and oviduct were hypotrophic and the oviduct was highly disorganized. Natural mating of Dicer1(fl/fl);Amhr2(Cre/+) females resulted in successful fertilization as evidenced by the recovery of fertilized oocytes on day 1 of pregnancy which developed normally to blastocysts in culture. Developmentally delayed embryos were collected from Dicer1(fl/fl);Amhr2(Cre/+) mice on day 3 of pregnancy when compared to controls. Oviductal transport was disrupted in the Dicer1(fl/fl);Amhr2(Cre/+) mouse as evidenced by the failure of embryos to enter the uterus on day 4 of pregnancy. These studies implicate Dicer1/miRNA mediated post-transcriptional gene regulation in reproductive somatic tissues as critical for the normal development and function of these tissues and for female fertility.

Species: mouse
Mutation name: None
type: null mutation
fertility: infertile - ovarian defect
Comment: Critical roles for Dicer in the female germline. Murchison EP et al. Dicer is an essential component of RNA interference (RNAi) pathways, which have broad functions in gene regulation and genome organization. Probing the consequences of tissue-restricted Dicer loss in mice indicates a critical role for Dicer during meiosis in the female germline. Mouse oocytes lacking Dicer arrest in meiosis I with multiple disorganized spindles and severe chromosome congression defects. Oogenesis and early development are times of significant post-transcriptional regulation, with controlled mRNA storage, translation, and degradation. Our results suggest that Dicer is essential for turnover of a substantial subset of maternal transcripts that are normally lost during oocyte maturation. Furthermore, we find evidence that transposon-derived sequence elements may contribute to the metabolism of maternal transcripts through a Dicer-dependent pathway. Our studies identify Dicer as central to a regulatory network that controls oocyte gene expression programs and that promotes genomic integrity in a cell type notoriously susceptible to aneuploidy.

Species: mouse
Mutation name: None
type: null mutation
fertility: infertile - ovarian defect
Comment: MicroRNA function is globally suppressed in mouse oocytes and early embryos. Suh N et al. Dicer, which is required for the processing of both microRNAs (miRNAs) and small interfering RNAs (siRNAs), is essential for oocyte maturation [1, 2]. Oocytes express both miRNAs and endogenous siRNAs (endo-siRNAs) [3, 4]. To determine whether the abnormalities in Dicer knockout oocytes during meiotic maturation are secondary to the loss of endo-siRNAs and/or miRNAs, we deleted Dgcr8, which encodes an RNA-binding protein specifically required for miRNA processing. In striking contrast to Dicer, Dgcr8-deficient oocytes matured normally and, when fertilized with wild-type sperm, produced healthy-appearing offspring, even though miRNA levels were reduced to similar levels as Dicer-deficient oocytes. Furthermore, the deletion of both maternal and zygotic Dgcr8 alleles did not impair preimplantation development, including the determination of the inner cell mass and trophectoderm. Most surprisingly, the mRNA profiles of wild-type and Dgcr8 null oocytes were essentially identical, whereas Dicer null oocytes showed hundreds of misregulated transcripts. These findings show that miRNA function is globally suppressed during oocyte maturation and preimplantation development and that endo-siRNAs, rather than miRNAs, underlie the Dicer knockout phenotype in oocytes.

Species: mouse
Mutation name: None
type: null mutation
fertility: None
Comment: Murine Follicular Development Requires Oocyte DICER, but Not DROSHA. Yuan S 2014 et al. Both DICER and DROSHA are RNase III enzymes involved in the biogenesis of small noncoding RNAs. DROSHA cleaves the stem-loop portion of the primary miRNAs and produces precursor miRNAs in the nucleus, whereas DICER processes double-stranded RNA precursors into mature miRNAs and endo-siRNAs in the cytoplasm. Selective inactivation of Dicer in growing oocytes of primary follicles leads to female infertility due to oocyte spindle defects. However, it remains unknown if oocyte Dicer expression in the fetal ovary is required for proper follicular development in the postnatal ovary. Moreover, the role of Drosha in folliculogenesis has never been investigated. Here, we report that conditional knockout of Dicer in prophase I oocytes of the fetal ovary led to compromised folliculogenesis, premature ovarian failure and female infertility in the adult ovary, whereas selective inactivation of Drosha in oocytes of either the fetal or the developing ovary had no effects on normal folliculogenesis and female fertility in adulthood. Our data indicate that oocyte DICER expression in the fetal ovary is required, and oocyte DROSHA is dispensable, for postnatal follicular development and female fertility in adulthood. /////////////////////////

Species: human
Mutation name:
type: naturally occurring
fertility: fertile
Comment: Functional characterization of multiple DICER1 mutations in an adolescent. Wu MK et al. (2015) DICER1 is an endoribonuclease which catalyzes the generation of mature 5p and 3p miRNAs. We present the detailed molecular characterization of three DICER1 mutations occurring in a child with multinodular goitre (MNG) and an ovarian sex cord-stromal tumor (OSCST), conditions associated with the DICER1 syndrome (OMIM 601200). We identified three DICER1 mutations affecting the RNase IIIb domain in the child: a novel germ-line DICER1 mutation (c.5441C>T) which does not affect the metal ion binding residues of RNase IIIb, and two different somatic mutations (5425G>T in the MNG and c.5125G>A in the OSCST), both situated at these metal ion binding residues. In vitro functional studies of the germ-line DICER1 (c.5441C>T) mutation showed that both 5p and 3p miRNAs were decreased, whereas the somatic mutation occurring in the MNG, c. 5425G>T, is predicted to function either as a missense (p.D1810Y) or a cryptic splice site (p.K1844fsX17). When the latter, no miRNAs are made. We also identified the previously studied c.5125G>A (p.D1709N) mutation in the OSCST. Following identification of the c.5125G>A, review of the original diagnosis of the OSCST (adult granulosa cell tumour) was revised to Sertoli-Leydig cell tumour, illustrating how molecular analysis can assist in the diagnosis of uncommon ovarian neoplasms. We also report the first instance of biallelic DICER1 mutations in a MNG. The three single base pair substitutions in DICER1 all affect the RNase IIIb domain, but have different effects on miRNA generation. This study demonstrates that detailed functional characterisation of DICER1 missense mutations may be required to determine pathogenicity.//////////////////

Species: mouse
Mutation name:
type: targeted overexpression
fertility: None
Comment: Constitutive Dicer1 phosphorylation accelerates metabolism and aging in vivo. Aryal NK et al. PNAS (2018)//////////////////

Species: human
Mutation name:
type: naturally occurring
fertility: fertile
Comment: Gynecologic and reproductive health in patients with pathogenic germline variants in DICER1. Merideth MA et al. (2020) Germline pathogenic variation in DICER1 underlies a tumor-predisposition disorder with increased risk for cervical embryonal rhabdomyosarcoma and ovarian sex-cord stromal tumors, particularly Sertoli-Leydig cell tumors. The gynecologic and reproductive health of these females has not yet been described. All female subjects recruited from November 2011 to July 2018 participating in an epidemiologic study of families with pathogenic DICER1 germline variation were included in this cross-sectional analysis. Participant evaluation included obstetric-gynecologic history, physical examination, hormone testing, pelvic ultrasound and record review. Of 64 females aged 2-72 years, fifteen underwent treatment for pleuropulmonary blastoma as children and three were treated for cervical embryonal rhabdomyosarcoma. Of nine patients reporting a history of ovarian tumors, all presented with virilization or amenorrhea; eight occurred in adolescence. Post-pubertal females with no history of ovarian tumors experienced normal pubertal development, reported regular menstrual cycles, were fertile and underwent natural menopause at median age of 52 years. Thirty-two of 33 women who tried to conceive successfully delivered liveborn children. Of these 32, 10 experienced pregnancy-related thyroid enlargement resulting in thyroidectomy within one year of pregnancy; nine others had undergone pre-pregnancy thyroidectomy. In these DICER1-carrier females, DICER1-related gynecological tumors occurred during childhood or adolescence in some after which women generally experienced healthy reproductive lives. Individual education and screening for these tumors is warranted. The high rate of DICER1-related multinodular goiter resulting in pre- and post-pregnancy thyroidectomy underscores the importance of thyroid monitoring during pregnancy to ensure maternal and fetal wellbeing.//////////////////