eIF4A controls germline stem cell self-renewal by directly inhibiting BAM function in the Drosophila ovary

Stem cell self-renewal is controlled by concerted actions of extrinsic niche signals and intrinsic factors in a variety of systems. Drosophila ovarian germline stem cells (GSCs) have been one of the most productive systems for identifying the factors controlling self-renewal. The differentiation factor BAM is necessary and sufficient for GSC differentiation, but it still remains expressed in GSCs at low levels. However, it is unclear how its function is repressed in GSCs to maintain self-renewal. Here, we report the identification of the translation initiation factor eIF4A for its essential role in self-renewal by directly inactivating BAM function. eIF4A can physically interact with BAM in Drosophila S2 cells and yeast cells. eIF4A exhibits dosage-specific interactions with bam in the regulation of GSC differentiation. It is required intrinsically for controlling GSC self-renewal and proliferation but not survival. In addition, it is required for maintaining E-cadherin expression but not BMP signaling activity. Furthermore, BAM and BGCN together repress translation of E-cadherin through its 3′ UTR in S2 cells. Therefore, we propose that BAM functions as a translation repressor by interfering with translation initiation and eIF4A maintains self-renewal by inhibiting BAM function and promoting E-cadherin expression.

[1]  M. Hentze,et al.  Using the lambdaN peptide to tether proteins to RNAs. , 2004, Methods in molecular biology.

[2]  Willis X. Li,et al.  A novel function of Drosophila eIF4A as a negative regulator of Dpp/BMP signalling that mediates SMAD degradation , 2006, Nature Cell Biology.

[3]  Ting Xie,et al.  decapentaplegic Is Essential for the Maintenance and Division of Germline Stem Cells in the Drosophila Ovary , 1998, Cell.

[4]  A. Spradling,et al.  The Drosophila ovarian and testis stem cell niches: similar somatic stem cells and signals. , 2005, Developmental cell.

[5]  Linheng Li,et al.  Stem cell niche: structure and function. , 2005, Annual review of cell and developmental biology.

[6]  A. Hinnebusch,et al.  Regulation of Translation Initiation in Eukaryotes: Mechanisms and Biological Targets , 2009, Cell.

[7]  Haifan Lin,et al.  Regulatory Relationship among piwi, pumilio, and bag-of-marbles in Drosophila Germline Stem Cell Self-Renewal and Differentiation , 2005, Current Biology.

[8]  M. Hentze,et al.  Tethered-function analysis reveals that elF4E can recruit ribosomes independent of its binding to the cap structure. , 2001, RNA.

[9]  D. Mckearin,et al.  Ectopic expression of the Drosophila Bam protein eliminates oogenic germline stem cells. , 1997, Development.

[10]  S. Hyberts,et al.  PDCD4 inhibits translation initiation by binding to eIF4A using both its MA3 domains , 2008, Proceedings of the National Academy of Sciences.

[11]  A. Spradling,et al.  bag-of-marbles: a Drosophila gene required to initiate both male and female gametogenesis. , 1990, Genes & development.

[12]  K. Abe,et al.  Conserved Role of nanos Proteins in Germ Cell Development , 2003, Science.

[13]  Haifan Lin,et al.  Yb modulates the divisions of both germline and somatic stem cells through piwi- and hh-mediated mechanisms in the Drosophila ovary. , 2001, Molecular cell.

[14]  Ting Xie,et al.  Germline Stem Cells Anchored by Adherens Junctions in the Drosophila Ovary Niches , 2002, Science.

[15]  Sean J. Morrison,et al.  Stem Cells and Niches: Mechanisms That Promote Stem Cell Maintenance throughout Life , 2008, Cell.

[16]  Ting Xie,et al.  Differentiation-defective stem cells outcompete normal stem cells for niche occupancy in the Drosophila ovary. , 2008, Cell stem cell.

[17]  A. Spradling,et al.  The Drosophila fusome, a germline-specific organelle, contains membrane skeletal proteins and functions in cyst formation. , 1994, Development.

[18]  T. Tabata,et al.  Daughters against dpp modulates dpp organizing activity in Drosophila wing development , 1997, Nature.

[19]  J. McCarthy,et al.  Bmp signals from niche cells directly repress transcription of a differentiation-promoting gene, bag of marbles, in germline stem cells in the Drosophila ovary , 2004, Development.

[20]  Haifan Lin,et al.  A novel class of evolutionarily conserved genes defined by piwi are essential for stem cell self-renewal. , 1998, Genes & development.

[21]  T. Xie,et al.  The Drosophila ovary: an active stem cell community , 2007, Cell Research.

[22]  Dahua Chen,et al.  A discrete transcriptional silencer in the bam gene determines asymmetric division of the Drosophila germline stem cell , 2003, Development.

[23]  D. Mckearin,et al.  A role for the Drosophila bag-of-marbles protein in the differentiation of cystoblasts from germline stem cells. , 1995, Development.

[24]  Min Han,et al.  GW182 family proteins are crucial for microRNA-mediated gene silencing. , 2007, Trends in cell biology.

[25]  A. Spradling,et al.  A niche maintaining germ line stem cells in the Drosophila ovary. , 2000, Science.

[26]  B. Edgar,et al.  Cell-autonomous and non-autonomous growth-defective mutants of Drosophila melanogaster. , 1999, Development.

[27]  D. Mckearin,et al.  The Drosophila cystoblast differentiation factor, benign gonial cell neoplasm, is related to DExH-box proteins and interacts genetically with bag-of-marbles. , 2000, Genetics.

[28]  Dahua Chen,et al.  Dpp Signaling Silences bam Transcription Directly to Establish Asymmetric Divisions of Germline Stem Cells , 2003, Current Biology.

[29]  M. Hentze,et al.  Using the λN Peptide to Tether Proteins to RNAs , 2004 .

[30]  J. Kimble,et al.  Controls of germline stem cells, entry into meiosis, and the sperm/oocyte decision in Caenorhabditis elegans. , 2007, Annual review of cell and developmental biology.

[31]  Dahua Chen,et al.  Gene Circuitry Controlling a Stem Cell Niche , 2005, Current Biology.