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Dicer1 Is Essential for Female Fertility and Normal Development of the Female Reproductive System

Departments of Molecular and Integrative Physiology (X.H., L.J.L., L.K.M., W.B.N., L.K.C.) and Obstetrics and Gynecology (W.B.N.), University of Kansas Medical Center, Kansas City, Kansas 66160

Address all correspondence and requests for reprints to: Lane K. Christenson, Department of Molecular and Integrative Physiology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, Kansas 66160. E-mail: lchristenson{at}kumc.edu.

The ribonuclease III endonuclease, Dicer1 (also known as Dicer), is essential for the synthesis of the 19–25 nucleotide noncoding RNAs known as micro-RNAs (miRNAs). These miRNAs associate with the RNA-induced silencing complex to regulate gene expression posttranscriptionally by base pairing with 3'untranslated regions of complementary mRNA targets. Although it is established that miRNAs are expressed in the reproductive tract, their functional role and effect on reproductive disease remain 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-müllerian 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 d 1 pregnancy, which developed normally to blastocysts in culture. Developmentally delayed embryos were collected from Dicer1^fl/fl; Amhr2^Cre/+ mice on d 3 pregnancy when compared with 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 d 4 pregnancy. These studies implicate Dicer1/miRNA mediated posttranscriptional gene regulation in reproductive somatic tissues as critical for the normal development and function of these tissues and for female fertility.

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