ANRV260-GE39-09 ARI 15 October 2005 12:5Molecular Mechanisms ofGermline Stem CellRegulationMarco D. Wong, Zhigang Jin, and Ting XieStowers Institute for Medical Research, Kansas City, Missouri 64110;email: [email protected]. Rev. Genet.2005. 39:173–95First published online as aReview in Advance onAugust 30, 2005The Annual Review ofGenetics is online athttp://genet.annualreviews.orgdoi: 10.1146/annurev.genet.39.073003.105855Copyrightc 2005 byAnnual Reviews. All rightsreserved0066-4197/05/1215-0173$20.00Key Wordsgermline stem cells, self-renewal, differentiation, niche,asymmetric cell divisionAbstractGermline stem cells (GSCs), which can self-renew and generate dif-ferentiated progeny, are unique stem cells in that they are solelydedicated to reproduction and transmit genetic information fromgeneration to generation. Through the use of genetic techniques inDrosophila, Caenorhabditis elegans, and mouse, exciting progress hasbeen made in understanding molecular mechanisms underlying in-teractions between stem cells and niches. The knowledge gainedfrom studying GSCs has provided an intellectual framework fordefining niches and molecular regulatory mechanisms for other adultstem cells. In this review, we summarize recent progress and discussconserved mechanisms underlying GSC self-renewal and differen-tiation by comparing three GSC systems. Because GSCs and otheradult stem cells share “stemness,” we hope this review will help definefundamental principles of stem cell regulation and provide furtherguidance for future studies of other adult stem cells.173Annu. Rev. Genet. 2005.39:173-195. Downloaded from arjournals.annualreviews.orgby University of California - San Diego on 09/16/06. For personal use only.ANRV260-GE39-09 ARI 15 October 2005 12:5ContentsINTRODUCTION................. 174REGULATORY MECHANISMSOF GERMLINE STEM CELLSELF-RENEWAL ANDDIFFERENTIATION IN THEDROSOPHILA OVARY .......... 175General Features of the DrosophilaOvarian GSCs and theirNiche......................... 175BMP, Piwi, and Yb Function in theNiche to Regulate theMaintenance and Division ofGSCs ........................ 175Intrinsic Factors Play EssentialRoles in GSC Maintenance andDifferentiation ................... 178Extrinsic Signals Regulate theFunction of Intrinsic Factors toControl GSC Self-Renewal andDifferentiation ................... 179REGULATORY MECHANISMSOF GERMLINE STEM CELLSELF-RENEWAL ANDDIFFERENTIATION IN THEDROSOPHILA TESTIS .......... 180General Features of the DrosophilaTesticular GSCs and theirNiche......................... 180Niche Signals, BMP and Unpaired,Control Testicular GSCSelf-Renewal .................. 180Different Classes of IntracellularFactors Regulate TesticularGSCs ......................... 182REGULATORY MECHANISMSOF GERM CELL FATESPECIFICATION INC. ELEGANS .................... 182General Features of the C. elegansGSCs and their Niche ......... 182A Notch-Like Signal from theDTC is Both Necessary andSufficient for Controlling GSCSelf-Renewal andProliferation .................. 183Intrinsic Factors Regulating RNAStability and Translation PlayEssential Roles in GSCMaintenance andDifferentiation ................ 183Interplay Between Notch-LikeSignaling and Intrinsic FactorsIs Critical for Controlling GSCSelf-Renewal andDifferentiation ................ 184REGULATORY MECHANISMSOF GERMLINE STEM CELLSELF-RENEWAL ANDDIFFERENTIATION INMAMMALS ..................... 184General Features of the MouseGSCs and their PutativeNiche......................... 184Signals from Sertoli Cells Controlthe Maintenance andDifferentiation of GSCs . . . .... 185Different Classes of IntrinsicFactors Control GSCMaintenance andDifferentiation in the MouseTestis ......................... 186SUMMARY AND FUTUREDIRECTIONS .................. 187INTRODUCTIONWith their remarkable ability to self-renewand undergo differentiation, stem cells arecrucial to development and tissue homeostasis(68, 88). Interest in stem cell research has bur-geoned since the successful culture of humanembryonic stem cells (hESCs), which are ableto generate various differentiated cell types(81, 92). In addition to ESCs, stem cells in avariety of adult tissues are also able to generate174 Wong·Jin·XieAnnu. Rev. Genet. 2005.39:173-195. Downloaded from arjournals.annualreviews.orgby University of California - San Diego on 09/16/06. For personal use only.ANRV260-GE39-09 ARI 15 October 2005 12:5one or several differentiated cell typesthroughout an individual’s lifetime. Germlinestem cells (GSC) are dedicated to producinggametes for transmission of genetic infor-mation from generation to generation and,therefore, are true “immortal stem cells.” Thesterility resulting from GSC loss can be eas-ily recognized, and it facilitates the identifi-cation of extrinsic signals and intrinsic factorsin genetic model systems such as Drosophila,C. elegans, and mouse. Furthermore, GSCsare easily identified in the anatomically simpleDrosophila ovary and testis and have enabledthe first elucidation of relationships betweenstem cells and their microenvironment or“niche” (48, 95, 105). The investigation of theGSC niche and the regulatory mechanisms ofstem cell self-renewal in Drosophila has pro-vided guiding principles for study of adultstem cells in other systems, because relation-ships between stem cells and their niches areconserved. Cultured mouse GSCs and stemcell transplantation make it feasible to elu-cidate molecular regulatory mechanisms ofmammalian GSCs (44, 53). This review sum-marizes our current understanding of GSCregulation, highlights conserved molecularmechanisms, and predicts future challenges.REGULATORY MECHANISMS OFGERMLINE STEM CELLSELF-RENEWAL ANDDIFFERENTIATION IN THEDROSOPHILA OVARYGeneral Features of the DrosophilaOvarian GSCs and their NicheThe identification of stem cells poses uniquechallenges particularly in mammalian systemsbecause stem cells are rare and indistinguish-able from early differentiated progeny (68,88). The Drosophila ovarian GSC system cir-cumvents this problem by virtue of its sim-ple anatomy, unique molecular markers, anda linear arrangement between stem cells andtheir differentiated progeny (30, 60, 102). Atthe tip of the germarium, the anterior endStem cell: a uniqueundifferentiated cellthat has the ability toself-renew andgeneratedifferentiated celltypesGSC: germline stemcellIntrinsic factors:factors that actwithin the cell tocontrol its behaviorNiche: themolecular milieu