The Drosophila Female Germline Stem Cell Lineage Acts to Spatially Restrict DPP Function Within the Niche

Drosophila ovarian stem cells communicate with somatic cells to define the size of the stem cell niche. Identifying with One’s Niche The stem cell niche in the Drosophila germarium (which produces egg chambers) supports two to three self-renewing germline stem cells (GSCs) surrounded by various types of somatic cells. The morphogen Decapentaplegic (DPP), which is produced by somatic cells in the niche, defines the spatial limits of the niche. Cells inside the niche are exposed to high concentrations of DPP and are maintained as stem cells, whereas cells located outside the niche receive lower concentrations and differentiate. However, it has been unclear how DPP activity is spatially restricted. Liu et al. found that when GSCs lacked functional Stet, an intramembrane protease that processes precursors of EGFR ligands into their mature forms, epidermal growth factor receptor (EGFR) signaling in somatic cells decreased, thereby increasing the expression of a glypican necessary for DPP stability and transport. Thus, mutant germaria for stet contained more cells that were activated by DPP and had more GSC-like cells than did wild-type germaria, indicating an expanded range for DPP function and, consequently, niche activity. These results suggest that GSCs play an active role in defining the size of the niche. Maintenance of stem cells requires spatially restricted, niche-associated signals. In the Drosophila female germline stem cell (GSC) niche, Decapentaplegic (DPP) is the primary niche-associated factor and functions over a short range to promote GSC self-renewal rather than differentiation. Here, we show that the GSC lineage and, more specifically, the stem cells themselves participate in the spatial restriction of DPP function by activating epidermal growth factor receptor (EGFR)–mitogen-activated protein kinase (MAPK) signaling in the surrounding somatic cells. EGFR-MAPK signaling in somatic cells repressed the expression of dally, which encodes a glypican required for DPP movement and stability. Consequently, only GSCs close to the DPP source (the somatic cells in the niche) showed high signal activation and were maintained as stem cells, whereas cystoblasts outside the niche showed low signal activation and initiated differentiation. Thus, our data reveal that the reciprocal crosstalk between the GSCs and the somatic cells defines the spatial limits of DPP action and therefore the extent of the GSC niche.

[1]  Liwei Wang,et al.  Dynein-mediated apical localization of crumbs transcripts is required for Crumbs activity in epithelial polarity , 2008, The Journal of cell biology.

[2]  Liwei Wang,et al.  The JAK/STAT pathway positively regulates DPP signaling in the Drosophila germline stem cell niche , 2008, The Journal of cell biology.

[3]  D. Branton,et al.  Drosophila spectrin. II. Conserved features of the alpha-subunit are revealed by analysis of cDNA clones and fusion proteins , 1987, The Journal of cell biology.

[4]  L. Stevens,et al.  Investigating the function of follicular subpopulations during Drosophila oogenesis through hormone-dependent enhancer-targeted cell ablation. , 2000, Development.

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

[6]  Sean J. Morrison,et al.  Asymmetric and symmetric stem-cell divisions in development and cancer , 2006, Nature.

[7]  O. Shimmi,et al.  Dally regulates Dpp morphogen gradient formation by stabilizing Dpp on the cell surface. , 2008, Developmental biology.

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

[9]  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.

[10]  E. Fuchs,et al.  Socializing with the Neighbors Stem Cells and Their Niche , 2004, Cell.

[11]  Y. Yarden,et al.  SnapShot: EGFR Signaling Pathway , 2007, Cell.

[12]  M. Freeman,et al.  A family of Rhomboid intramembrane proteases activates all Drosophila membrane‐tethered EGF ligands , 2002, The EMBO journal.

[13]  T. Xie,et al.  wingless signaling regulates the maintenance of ovarian somatic stem cells in Drosophila , 2003, Development.

[14]  N. Perrimon,et al.  Mechanism of activation of the Drosophila EGF Receptor by the TGFalpha ligand Gurken during oogenesis. , 2002, Development.

[15]  Howard Y. Chang,et al.  Bone morphogenetic protein antagonist gremlin 1 is widely expressed by cancer-associated stromal cells and can promote tumor cell proliferation , 2006, Proceedings of the National Academy of Sciences.

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

[17]  S. Tazuke,et al.  Signaling from germ cells mediated by the rhomboid homolog stet organizes encapsulation by somatic support cells. , 2002, Development.

[18]  Allan C. Spradling Developmental Genetics of oogenesis , 1993 .

[19]  S. Tazuke,et al.  Antagonistic Roles of Rac and Rho in Organizing the Germ Cell Microenvironment , 2007, Current Biology.

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

[21]  Yukiko M Yamashita,et al.  Signaling in stem cell niches: lessons from the Drosophila germline , 2005, Journal of Cell Science.

[22]  B. Shilo,et al.  Signaling by the Drosophila epidermal growth factor receptor pathway during development. , 2003, Experimental cell research.

[23]  M. Ronshaugen,et al.  brother of rhomboid, a rhomboid-related gene expressed during early Drosophila oogenesis, promotes EGF-R/MAPK signaling. , 2000, Developmental biology.

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

[25]  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.

[26]  M. Freeman,et al.  Complexity of EGF receptor signalling revealed in Drosophila. , 1998, Current opinion in genetics & development.

[27]  A. Spradling,et al.  The expression profile of purified Drosophila germline stem cells. , 2005, Developmental biology.

[28]  Haifan Lin The stem-cell niche theory: lessons from flies , 2002, Nature Reviews Genetics.

[29]  A. Spradling,et al.  Stem cells find their niche , 2001, Nature.

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

[31]  A. Spradling,et al.  An empty Drosophila stem cell niche reactivates the proliferation of ectopic cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[32]  T. Tabata,et al.  Hedgehog creates a gradient of DPP activity in Drosophila wing imaginal discs. , 2000, Molecular cell.

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

[34]  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.

[35]  T. Matsuo,et al.  Dally regulates Dpp morphogen gradient formation in the Drosophila wing , 2003, Development.

[36]  H. Ruohola-Baker,et al.  Stem Cells Signal to the Niche through the Notch Pathway in the Drosophila Ovary , 2006, Current Biology.

[37]  A. Spradling,et al.  Identification and behavior of epithelial stem cells in the Drosophila ovary. , 1995, Development.

[38]  A. Spradling,et al.  Male and Female Drosophila Germline Stem Cells: Two Versions of Immortality , 2007, Science.

[39]  B. Shilo,et al.  In situ activation pattern of Drosophila EGF receptor pathway during development. , 1997, Science.

[40]  J. H. Sang,et al.  The Drosophila Ovary , 1970 .

[41]  P. Ingham,et al.  hedgehog is required for the proliferation and specification of ovarian somatic cells prior to egg chamber formation in Drosophila. , 1996, Development.

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

[43]  Gerald B Call,et al.  Notch signaling controls germline stem cell niche formation in the Drosophila ovary , 2007, Development.

[44]  D. Burns,et al.  Neurofibromas in NF1: Schwann Cell Origin and Role of Tumor Environment , 2002, Science.

[45]  Xinhua Lin,et al.  Drosophila Dpp Morphogen Movement Is Independent of Dynamin-Mediated Endocytosis but Regulated by the Glypican Members of Heparan Sulfate Proteoglycans , 2004, Cell.

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

[47]  A. Spradling,et al.  Germline stem cell division and egg chamber development in transplanted Drosophila germaria. , 1993, Developmental biology.

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

[49]  A. Spradling,et al.  Fusome asymmetry and oocyte determination in Drosophila. , 1995, Developmental genetics.