PT - JOURNAL ARTICLE AU - Katherine Kretovich Billmyre AU - Bree Heestand AU - Maya Spichal AU - Stephen Frenk AU - Shawn Ahmed TI - Transgenerational sterility of Piwi pathway mutants in response to germ granule dysfunction AID - 10.1101/276782 DP - 2018 Jan 01 TA - bioRxiv PG - 276782 4099 - http://biorxiv.org/content/early/2018/04/25/276782.short 4100 - http://biorxiv.org/content/early/2018/04/25/276782.full AB - Germ cells deficient for Piwi and associated small RNA genome silencing factors transmit a form of heritable stress that induces sterility after growth for several generations. The cause of this transgenerational sterility phenotype is not understood but has been attributed to progressive deterioration of heterochromatin and associated DNA damage. Sterile small RNA genome silencing mutants displayed inconsistent increases in DNA damage signaling but consistently altered perinuclear germ granules. Germ granule dysfunction was sufficient to induce phenotypes associated with sterile small RNA genome silencing mutants, including germline atrophy, reproductive diapause and univalents in oocytes. Genes that perturb germ granule structure were not compromised in sterile small RNA mutants, suggesting a post-transcriptional reproductive arrest mechanism. We conclude that the integrity of germ granules, which are intimately associated with Piwi silencing factors, orchestrates the sterility of Piwi deficient mutants and could be generally relevant to regulation of reproductive arrest in response to stress.Significance Statement Sterility in response to heterochromatin dysfunction was recognized in Drosophila P-M Hybrid Dysgenesis experiments carried out by Margaret Kidwell in the 1970’s and more recently in mutants deficient for Piwi/piRNA silencing. A central model of these studies is that this sterility is caused by transposon expression and associated genomic instability. We demonstrate that sterility in response to deficiency for Piwi is a form of reproductive arrest that is orchestrated by germ granule dysfunction. Germ granules promote genomic silencing of transposons and viruses, and they are likely to be frequently targeted by these parasites. We hypothesize the evolution of a reproductive arrest mechanism that responds to attacks on germ granules by disrupting their integrity.