Declining levels of miR-382-3p at puberty trigger the onset of spermatogenesis

Alka Gupta; Kamal Mandal; Parminder Singh; Rajesh Sarkar; Subeer S Majumdar

doi:10.1016/j.omtn.2021.07.001

Declining levels of miR-382-3p at puberty trigger the onset of spermatogenesis

Mol Ther Nucleic Acids. 2021 Jul 16:26:192-207. doi: 10.1016/j.omtn.2021.07.001. eCollection 2021 Dec 3.

Authors

Alka Gupta¹, Kamal Mandal¹, Parminder Singh², Rajesh Sarkar¹, Subeer S Majumdar^{1

3}

Affiliations

¹ Cellular Endocrinology Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India.
² Metabolic Research Laboratory, National Institute of Immunology, New Delhi, India.
³ Genes and Protein Engineering Laboratory, National Institute of Animal Biotechnology, Hyderabad, India.

Abstract

A major change in the transcriptome of testicular Sertoli cells (Scs) at the onset of puberty enables them to induce robust spermatogenesis. Through comprehensive literature mining, we generated a list of genes crucial for Sc functioning and computationally predicted the microRNAs regulating them. Differential expression analysis of microRNAs in infant and pubertal rat Scs showed that miR-382-3p levels decline significantly in pubertal Scs. Interestingly, miR-382-3p was found to regulate genes like Ar and Wt1, which are crucial for functional competence of Scs. We generated a transgenic (Tg) mouse model in which pubertal decline of miR-382-3p was prevented by its overexpression in pubertal Scs. Elevated miR-382-3p restricted the functional maturation of Scs at puberty, leading to infertility. Prevention of decline in miR-382-3p expression in pubertal Scs was responsible for defective blood-testis barrier (BTB) formation, severe testicular defects, low epididymal sperm counts and loss of fertility in these mice. This provided substantial evidence that decline in levels of miR-382-3p at puberty is the essential trigger for onset of robust spermatogenesis at puberty. Hence, sustained high levels of miR-382-3p in pubertal Scs could be one of the underlying causes of idiopathic male infertility and should be considered for diagnosis and treatment of infertility.

Keywords: Sertoli cell; blood-testis barrier; infertility; microRNAs; spermatogenesis; transgenic mice.