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Published on: October 11, 2015
Deficiency in DGCR8-dependent canonical microRNAs causes infertility due to multiple abnormalities during uterine
Yeon Sun Kim1, Hye-Ryun Kim1, Hyongbum Kim2
1Department of Biomedical Science, CHA University, Seongnam, Gyeonggi, 463-400 Korea.
Abstract:
DGCR8 is an RNA-binding protein that interacts with DROSHA to produce pre-microRNA in the nucleus, while DICER generates not only mature microRNA, but also endogenous small interfering RNAs in the cytoplasm. Here, we produced Dgcr8 conditional knock-out mice using progesterone receptor (PR)-Cre (Dgcr8(d/d)) and demonstrated that canonical microRNAs dependent on the DROSHA-DGCR8 complex are required for uterine development as well as female fertility in mice. Adult Dgcr8(d/d) females neither underwent regular reproductive cycles nor produced pups, whereas administration of exogenous gonadotropins induced normal ovulation in these mice. Interestingly, immune cells associated with acute inflammation aberrantly infiltrated into reproductive organs of pregnant Dgcr8(d/d) mice. Regarding uterine development, multiple uterine abnormalities were noticeable at 4 weeks of age when PR is significantly increased, and the severity of these deformities increased over time. Gland formation and myometrial layers were significantly reduced, and the stromal cell compartment did not expand and became atrophic during uterine development in these mice. These results were consistent with aberrantly reduced stromal cell proliferation and completely failed decidualization. Collectively, we suggest that DGCR8-dependent canonical microRNAs are essential for uterine development and physiological processes such as proper immune modulation, reproductive cycle, and steroid hormone responsiveness in mice.
Insights
DGCR8-dependent microRNAs are crucial for female fertility and uterine development in mice. Loss of DGCR8 disrupts reproductive cycles, causes uterine abnormalities, and impairs immune responses during pregnancy.
Area of Science:
- Reproductive Biology
- Molecular Biology
- Genetics
Background:
- DGCR8 (DiGeorge Critical Region 8) is an RNA-binding protein essential for microRNA biogenesis.
- The DROSHA-DGCR8 complex processes pre-microRNAs in the nucleus.
- Canonical microRNAs play vital roles in various physiological processes.
Purpose of the Study:
- To investigate the role of DGCR8-dependent canonical microRNAs in uterine development and female fertility.
- To elucidate the impact of DGCR8 deficiency on reproductive cycles and pregnancy outcomes.
Main Methods:
- Generation of Dgcr8 conditional knock-out mice using progesterone receptor (PR)-Cre (Dgcr8(d/d)).
- Assessment of reproductive cycles, ovulation, and pup production in Dgcr8(d/d) females.
- Histological and cellular analysis of uterine development and immune cell infiltration.
Main Results:
- Dgcr8(d/d) females exhibited impaired uterine development, including reduced gland formation and myometrial layers.
- These mice showed atrophic stromal compartments, failed decidualization, and reduced stromal cell proliferation.
- Adult Dgcr8(d/d) females were infertile, lacking regular reproductive cycles, but could ovulate with gonadotropin administration.
- Aberrant infiltration of immune cells was observed in the reproductive organs of pregnant Dgcr8(d/d) mice.
Conclusions:
- DGCR8-dependent canonical microRNAs are indispensable for normal uterine development and female fertility in mice.
- These microRNAs regulate key physiological processes including immune modulation, reproductive cyclicity, and steroid hormone responsiveness.
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