title: Drosophila piwi mutants exhibit germline stem cell tumors that are sustained by elevated Dpp signaling.
abstract: Drosophila Piwi is the founding member of a gonadal clade of Argonaute proteins that serve as silencing effectors for ∼26-32 nt Piwi-interacting RNAs (piRNAs) [1], and piwi mutants exhibit dramatically rudimentary ovaries [2]. It was proposed that somatic Piwi maintains germline stem cells (GSCs) by promoting Dpp signaling, presumably via cap cells that form the somatic niche for GSCs [3-5]. However, we unexpectedly observed that piwi mutants exhibit high-frequency GSC-like tumors that persist throughout adult life. Multiple readouts demonstrated hyperactive Dpp signaling in piwi mutants, including the failure to express the germline differentiation factor bag-of-marbles (bam), and restoration of bam expression relieved piwi GSC-like tumors. Tissue-specific rescue and knockdown experiments indicate that Piwi is not required in cap cells, the source of niche Dpp, but instead is required in gonadal intermingled cells (ICs, the progenitor cells of escort cells). Adult-specific knockdown of dpp in escort cells substantially rescued piwi tumors, demonstrating that they are driven by excess Dpp signaling. However, the temporal requirement for piwi to restrict GSC numbers was much earlier, during the wandering third-instar larval stage. Indeed, piwi mutant larval gonads exhibited defective morphology and loss of Bam. Our data indicate that loss of Piwi causes defects in ICs and escort cells, leading to ectopic Dpp signaling and consequent blockage of GSC differentiation.
authors.affiliation: Department of Developmental Biology, Sloan-Kettering Institute, 1275 York Avenue, Box 252, New York, NY 10065, USA.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Jin
authors.forename: Alex S
authors.initials: AS
authors.lastname: Flynt
authors.forename: Eric C
authors.initials: EC
authors.lastname: Lai
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D060565:Argonaute Proteins / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation; D004330:Drosophila / Q000235:genetics; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D007814:Larva / Q000235:genetics; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology*; D015398:Signal Transduction; D055153:Stem Cell Niche; D013234:Stem Cells / Q000473:pathology
chemical_list: D060565:Argonaute Proteins; D029721:Drosophila Proteins; C091674:bam protein, Drosophila; C064196:dpp protein, Drosophila; C116498:piwi protein, Drosophila
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