LAUSR

The post-meiotic phase of male germ cell development in mammals undergoes a series of dramatic morphological changes, including acrosome and flagellum formation, nuclear condensation, and cytoplasmic exclusion, which is driven by a highly regulated sequence of biochemical reactions (Meistrich and Hess, 2013). Such differentiation process called spermiogenesis consists of at least 16 sequential transition steps in mice, including steps 1 to 8 for round spermatids, steps 9 to 11 for elongating spermatids, steps 12 to 14 for elongated or condensed spermatids, and final steps 15 to 16 for spermatozoa (Meistrich and Hess, 2013). The sequential transitions are programmed by highly orchestrated regulatory events in gene expression at each developmental step, which is essential for round spermatids to transform into elongating and elongated spermatids and eventually into highly specialized spermatozoa. Due to chromatin compaction in the course of spermatid elongation, transcription becomes largely silenced at step 9 and completely ceased later on (Steger, 1999). Consequently, many mRNAs are transcribed earlier in spermatocytes and round spermatids and stored in translationally inert messenger ribonucleoproteins (mRNPs) until needed for translation (Steger, 1999). This phenomenon, known as uncoupling between transcription and translation, is a unique feature of gene regulation during spermiogenesis, which has been a major mystery in understanding the germ cell development program. The evolutionarily conserved PIWI proteins belong to the Piwi clade of the Argonaute family, each of which is specifically expressed in animal germlines and essential for germline development in animals (Iwasaki et al., 2015; Czech et al., 2018; Ozata et al., 2019). Drosophila PIWI proteins, consisting of AGO3, AUB and PIWI, are required for germ cell formation and germline stem cell maintenance. The murine PIWI homologs MIWI, MILI, and MIWI2 are specifically expressed in testis and are essential for spermatogenesis and male fertility in mice. The human genome encodes four Piwi family members, including Hiwi, Hili, Hiwi2, and Piwil3, all of which are highly expressed in testis. Despite that the function of PIWI proteins in human germline development has remained elusive, our recent study shows a causative role of Hiwi mutations in male infertility, establishing a definitive linkage of human Piwi genes to human infertility (Gou et al., 2017; Hasuwa et al., 2018). In 2006, PIWI proteins were reported to associate with a novel class of germ-cell-specific small noncoding RNAs, termed PIWIinteracting RNAs (piRNAs), by four independent groups (Iwasaki et al., 2015; Czech et al., 2018; Ozata et al., 2019). piRNAs range from 23 to 32 nt in length, originate from single-stranded precursors and are generated via a Dicerindependent mechanism. Instead, a number of germlinespecific protein factors, including PIWI proteins, are required for piRNA production (Iwasaki et al., 2015; Czech et