Current options for male birth control, such as condoms or vasectomies, mainly focus on blocking sperm transport. Now, a team led by researchers from Michigan State University have learned how to turn off sperm production in mice, paving a foundation for a different option for contraception.
The study revolves around the regulatory role of Piwi-interacting RNAs (piRNA) on transposons. Transposons are mobile genetic elements that hop into essential genes, disrupting them and and causing diseases. In the case of mice, certain transposons can cause male sterility. piRNAs are expressed in the germline and function to silence these transposons and ensure proper development of gametes.
Chen Chen, Ph.D. and his team have identified a protein, PNLDC1, previously implicated in trimming of piRNA, but whose function is relatively unknown. Chen's team has found that this function is in the silencing of transposons and for spermatogenesis.
Using CRISPR-Cas9 genome editing, Chen’s group has mutated mice to turn off the Pnldc-1 gene. What they have found was an accumulation of untrimmed piRNA intermediates, with longer 3’ ends. Accordingly, this has led to a severe reduction of mature piRNAs in the testis.
As expected, a well-known germline-acting transposon LINE1 that is normally silenced, is found to be elevated, confirmed by mRNA and Western blot analyses. An accompanying defect in spermiogenesis is also observed. Together, the findings identify PNLDC1 as a mammalian piRNA biogenesis factor, that if turned off, halts normal sperm production in mice.
Foundational work on understanding sperm production can have profound clinical implications, such as animal sterilization and human contraception. "More than 500,000 men get vasectomies every year," Chen says. "There's a huge market for this research, and now we further understand the genetic underpinnings of sperm development in mammals."
The findings have been published today in Nature Communications.