yama, a mutant allele of Mov10l1, disrupts retrotransposon silencing and piRNA biogenesis
Authors: Guan Yongjuan , Jain Devanshi , Keeney Scott , Wang P. Jeremy 
Published: November 2020

Piwi-interacting RNAs (piRNAs) play critical roles in protecting germline genome integrity and promoting normal spermiogenic differentiation. In mammals, there are two populations of piRNAs: pre-pachytene and pachytene piRNAs. Transposon-rich pre-pachytene piRNAs are expressed in fetal and perinatal germ cells and are required for retrotransposon silencing, whereas transposon-poor pachytene piRNAs are expressed in spermatocytes and round spermatids and regulate mRNA transcript levels. MOV10L1, a germ cell-specific RNA helicase, is essential for the production of both populations of piRNAs. Although the requirement of the RNA helicase domain located in the MOV10L1 C-terminal region for piRNA biogenesis is well known, its large N-terminal region remains mysterious. Here we report a novel Mov10l1 mutation in the Mov10l1 N-terminal region named yama. The yama mutation results in a single amino acid substitution V229E. The yama mutation causes meiotic arrest, de-repression of transposable elements, and male sterility because of defects in pre-pachytene piRNA biogenesis. Moreover, restricting the Mov10l1 mutation effects to later stages in germ cell development by combining with a postnatal conditional deletion of a complementing wild-type allele causes absence of pachytene piRNAs, accumulation of piRNA precursors, polar conglomeration of piRNA pathway proteins in spermatocytes, and spermiogenic arrest. Mechanistically, the V229E substitution in MOV10L1 reduces its interaction with PLD6, an endonuclease that generates the 5′ ends of piRNA intermediates. Our results uncover an important role for the MOV10L1-PLD6 interaction in piRNA biogenesis throughout male germ cell development.

Author Summary

Small non-coding RNAs play critical roles in silencing of exogenous viruses, endogenous retroviruses, and transposable elements, and also play multifaceted roles in controlling gene expression. Piwi-interacting RNAs (piRNAs) are found in gonads in diverse species from flies to humans. An evolutionarily conserved function of piRNAs is to silence transposable elements through an adaptive mechanism and thus to protect the germline genome integrity. In mammals, piRNAs also provide a poorly understood function to regulate postmeiotic differentiation of spermatids. More than two dozen proteins are involved in the piRNA pathway. MOV10L1, a germ-cell-specific RNA helicase, binds to piRNA precursors to initiate piRNA biogenesis. Here we have identified a single amino acid substitution (V229E) in MOV10L1 in the yama mutant. When constitutively expressed as the only source of MOV10L1 throughout germ cell development, the yama mutation abolishes piRNA biogenesis, de-silences transposable elements, and causes meiotic arrest. When the mutant phenotype is instead revealed only later in germ cell development by conditionally inactivating a complementing wild-type copy of the gene, the point mutant abolishes formation of later classes of piRNAs and again disrupts germ cell development. Point mutations in MOV10L1 may thus contribute to male infertility in humans.