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First published online 21 November 2007
doi: 10.1242/dev.006486

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Biogenesis and germline functions of piRNAs

Program in Molecular Medicine, Program in Cell Dynamics, University of Massachusetts Medical School, Worcester, MA 01605, USA.

View larger version (15K): [in this window] [in a new window]   Fig. 1. Ping-pong model for piRNA production. (A) The Piwi-class Argonaute protein Argonaute 3 (Ago3) binds to sense-strand piRNAs (blue) and directs the cleavage of target antisense-strand transcripts (red), producing the 5' end of antisense-strand piRNAs. (B) Aubergine (Aub) and Piwi (not shown) bind to the resulting piRNA precursor, which is trimmed to its final length. This might be catalyzed by the putative nucleases Squash and Zucchini. (C) Drosophila Hen1 methylates the 3' ends of piRNAs (3'OMe). (D) Aub-antisense-strand piRNA complexes catalyze the cleavage of sense transcripts (blue), producing the 5' end of sense piRNAs. (E) Ago3 binds the resulting sense piRNA precursors, which are trimmed and (F) methylated, as described for antisense-strand piRNAs. Based on the model proposed by Brennecke et al. (Brennecke et al., 2007).

View larger version (46K): [in this window] [in a new window]   Fig. 2. Compartmentalization of piRNA production and function. (A) Localization of Piwi-class Argonautes in the Drosophila ovary. Argonautes (red), DNA (blue). Argonaute 3 (Ago3, top) and Aubergine (Aub, middle) localize to the cytoplasm and nuage, which is a perinuclear structure rich in RNA-processing enzymes. Piwi (bottom) localizes predominantly to germline nuclei. (B) Model for compartmentalized production and function of piRNAs. (1) Sense (blue) and antisense (red) strands of piRNA `master control' regions are transcribed and (2) exported from the nucleus. (3) In the nuage, Aub-piRNA complexes cleave sense transcripts, leading to the production of sense-strand piRNAs that (4) associate with Ago3. (5) Ago3-piRNA complexes cleave antisense transcripts, producing piRNAs that (6) associate with Aub and Piwi. (7) Aub complexes remain in the nuage and cleave sense-strand complexes. (8) Piwi-piRNA complexes are imported into the nucleus, where they silence homologous genes in euchromatin and heterochromatin.

View larger version (104K): [in this window] [in a new window]   Fig. 3. The piRNA pathway is required for germline development. (A) piwi is required for the self-renewing division of germline stem cells during oogenesis. DAPI-stained images of 0- to 1-day-old adult ovarioles from wild-type (WT; +/+) and piwi2 Drosophila. WT ovarioles contain a long string of developing egg chambers produced through continuous stem cell division. By contrast, piwi mutant ovarioles typically contain only two egg chambers, derived through stem cell differentiation and loss. Ge, germarium; S1, stage 1 egg chamber [from Cox et al. (Cox et al., 1998)]. (B) Increased DNA damage in the germline cells of aub mutant ovaries. Drosophila ovaries immunostained to reveal the phosphorylated form of histone H2Av (-H2Av, red) and DNA (blue). -H2Av accumulates near double-strand break (DSB) sites. In WT ovaries, -H2Av foci are restricted to region 2 of the germarium, where meiotic DSBs form. In aub mutant ovaries, -H2Av foci accumulate in cells within the germarium and persist and increase in intensity only in the germline as cysts bud from the germarium to form egg chambers [from Klattenhoff et al. (Klattenhoff et al., 2007)]. (C) Miwi2 mutation depletes germ cell lineages in mouse testes. Hematoxylin and Eosin (HE) staining of WT and Miwi2 mutant adult testes shows germline degeneration in Miwi2 mutant mouse testes [from Carmell et al. (Carmell et al., 2007)]. (D) Ziwi is necessary for the maintenance of the zebrafish germline. HE staining shows that ziwi mutants have germ-cell-depleted testes, as compared with WT [from Houwing et al. (Houwing et al., 2007)]. (A) Reprinted with permission from Cold Spring Harbor Laboratory Press; (B,C,D) reprinted with permission from Elsevier.