The identification of new genes involved in sexual development and gonadal function as potential candidates causing male infertility is important for both diagnostic and therapeutic purposes. Deficiency of the onco-miRNA cluster miR-17∼92 has been shown to disrupt spermatogenesis, whereas mutations in its paralog cluster, miR-106b∼25, that is expressed in the same cells, were reported to have no effect on testis development and function. The aim of this work is to determine the role of these two miRNA clusters in spermatogenesis and male fertility. For this, we analysed miR-106b∼25 and miR-17∼92 single and double mouse mutants and compared them to control mice. We found that miR-106b∼25 knock out testes show reduced size, oligozoospermia and altered spermatogenesis. Transcriptomic analysis showed that multiple molecular pathways are deregulated in these mutant testes. Nevertheless, mutant males conserved normal fertility even when early spermatogenesis and other functions were disrupted. In contrast, miR-17∼92+/-;miR-106b∼25-/- double mutants showed severely disrupted testicular histology and significantly reduced fertility. Our results indicate that miR-106b∼25 and miR-17∼92 ensure accurate gene expression levels in the adult testis, keeping them within the required thresholds. They play a crucial role in testis homeostasis and are required to maintain male fertility. Hence, we have identified new candidate genetic factors to be screened in the molecular diagnosis of human males with reproductive disorders. Finally, considering the well known oncogenic nature of these two clusters and the fact that patients with reduced fertility are more prone to testicular cancer, our results might also help to elucidate the molecular mechanisms linking both pathologies.
Molecular human reproduction. 2020 Apr 24 [Epub ahead of print]
Alicia Hurtado, Rogelio Palomino, Ina Georg, Miguel Lao, Francisca M Real, F David Carmona, Miguel Burgos, Rafael Jiménez, Francisco J Barrionuevo
Departamento de Genética e Instituto de Biotecnología, Universidad de Granada, Labs 127 and 105a, Centro de Investigación Biomédica, Avenida del Conocimiento, Armilla, Granada, Spain., Departamento de Bioquímica y Biología Molecular I e Instituto de Investigación Biosanitaria de Granada, Universidad de Granada, Laboratorio 127 Centro de Investigación Biomédica, Avenida del Conocimiento, Armilla, Granada, Spain., Pfizer-University of Granada-Junta de Andalucía "Centre for Genomics and Oncological Research" (GENYO), Avenida de la Ilustración 114, Granada, Spain.