Oligoasthenoteratozoospermia and infertility in mice deficient for miR-34b/c and miR-449 loci
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Updated: Apr 21, 2026
Mouse Round Spermatid Injection
Published on: January 26, 2024
Stefano Comazzetto1, Monica Di Giacomo1, Kasper Dindler Rasmussen1
1European Molecular Biology Laboratory (EMBL), Mouse Biology Unit, Monterotondo Scalo, Italy.
Abstract:
Male fertility requires the continuous production of high quality motile spermatozoa in abundance. Alterations in all three metrics cause oligoasthenoteratozoospermia, the leading cause of human sub/infertility. Post-mitotic spermatogenesis inclusive of several meiotic stages and spermiogenesis (terminal spermatozoa differentiation) are transcriptionally inert, indicating the potential importance for the post-transcriptional microRNA (miRNA) gene-silencing pathway therein. We found the expression of miRNA generating enzyme Dicer within spermatogenesis peaks in meiosis with critical functions in spermatogenesis. In an expression screen we identified two miRNA loci of the miR-34 family (miR-34b/c and miR-449) that are specifically and highly expressed in post-mitotic male germ cells. A reduction in several miRNAs inclusive of miR-34b/c in spermatozoa has been causally associated with reduced fertility in humans. We found that deletion of both miR34b/c and miR-449 loci resulted in oligoasthenoteratozoospermia in mice. MiR-34bc/449-deficiency impairs both meiosis and the final stages of spermatozoa maturation. Analysis of miR-34bc-/-;449-/- pachytene spermatocytes revealed a small cohort of genes deregulated that were highly enriched for miR-34 family target genes. Our results identify the miR-34 family as the first functionally important miRNAs for spermatogenesis whose deregulation is causal to oligoasthenoteratozoospermia and infertility.
Insights
The miR-34 family of microRNAs is crucial for male fertility, regulating sperm production and quality. Their absence causes infertility by impairing sperm development and maturation.
Area of Science:
- Reproductive Biology
- Molecular Genetics
- Developmental Biology
Background:
- Male fertility depends on abundant, high-quality sperm production.
- Oligoasthenoteratozoospermia, characterized by low sperm count, motility, and abnormal morphology, is a primary cause of human infertility.
- Post-mitotic spermatogenesis is transcriptionally inert, suggesting a critical role for post-transcriptional gene regulation via microRNAs (miRNAs).
Purpose of the Study:
- To investigate the role of the miR-34 family (miR-34b/c and miR-449) in male germ cell development and spermatogenesis.
- To determine if the absence of these miRNAs causes male infertility.
Main Methods:
- Expression screening to identify miRNAs in male germ cells.
- Generation of knockout mice lacking miR-34b/c and miR-449 loci.
- Analysis of sperm parameters (count, motility, morphology) in knockout mice.
- Gene expression analysis in pachytene spermatocytes from knockout mice.
Main Results:
- The miR-34 family (miR-34b/c and miR-449) is specifically expressed in post-mitotic male germ cells.
- Deletion of miR-34b/c and miR-449 loci in mice resulted in oligoasthenoteratozoospermia.
- MiRNA deficiency impaired meiosis and sperm maturation.
- Gene expression analysis revealed deregulation of miR-34 family target genes in knockout spermatocytes.
Conclusions:
- The miR-34 family is essential for spermatogenesis and male fertility.
- Deregulation of the miR-34 family is a causal factor in oligoasthenoteratozoospermia and infertility.
- This study identifies the miR-34 family as the first functionally critical miRNAs for male germ cell development.
