SummaryGermline stem cells (GSCs) in Drosophila are a valuable model to explore of how adult stem cells are regulated in vivo. Genetic dissection of this system has shown that stem cell fate is determined and maintained by the stem cell's somatic microenvironment or niche. In Drosophila gonads, the stem cell niche-the cap cell cluster in females and the hub in males-acts as a signaling center to recruit GSCs from among a small population of undifferentiated primordial germ cells (PGCs). Shortrange signals from the niche specify and regulate stem cell fate by maintaining the undifferentiated state of the PGCs next to the niche. Germline cells that do not receive the niche signals because of their location assume the default fate and differentiate. Once GSCs are specified, adherens junctions maintain close association between the stem cells and their niche and help to orient stem cell division so that one daughter is displaced from the niche and differentiates. In females, stem cell fate depends on bone morphogenetic protein (BMP) signals from the cap cells; in males, hub cells express the cytokine-like ligand Unpaired, which activates the Janus kinase-signal transducers and activators of transcription (Jak-Stat) pathway in stem cells. Although the signaling pathways operating between the niche and stem cells are different, there are common general features in both males and females, including the arrangement of cell types, many of the genes used, and the logic of the system that maintains stem cell fate. KeywordsDrosophila; germline stem cell; GSC; PGC; primordial germ cell; stem cell fate; stem cell niche IntroductionStem cells are defined by their capacity to self-renew and to generate daughters that differentiate into one or more terminal cell types. Proper regulation of this property is critical for animal development, growth control, and reproduction. Understanding stem cell function is potentially very important for future developments in gene therapies and regenerative medicine. Research in Drosophila on germline stem cells (GSCs) has been instrumental in defining the important function of the stem cell's somatic microenvironment or niche in the control of its division and self-renewal (1,2). The Drosophila germline is an excellent model of stem cell biology because the system is genetically tractable, the sterility and rudimentary gonads resulting from GSC loss are easily recognized, and the stem cells can be easily identified based on molecular markers and position in the gonad. Germline morphology and development, from embryogenesis to the differentiation of gametes in adult flies, has been well characterized and offers a solid basis for the study of GSC fate determination, maintenance, and differentiation.Drosophila GSCs are derived from embryonic pole cells, the first cell type defined in the embryo. They migrate from the posterior to meet the somatic gonadal precursors (SGPs) and form the embryonic gonad, a simple structure made up of about ten primordial germ cells (PGCs) intermingled with and surr...
We describe the role of the Drosophila melanogaster hephaestusgene in wing development. We have identified several hephaestusmutations that map to a gene encoding a predicted RNA-binding protein highly related to human polypyrimidine tract binding protein and Xenopus laevis 60 kDa Vg1 mRNA-binding protein. Polypyrimidine tract binding proteins play diverse roles in RNA processing including the subcellular localization of mRNAs, translational control, internal ribosome entry site use, and the regulation of alternate exon selection. The analysis of gene expression in imaginal discs and adult cuticle of genetic mosaic animals supports a role for hephaestus in Notch signalling. Somatic clones lacking hephaestus express the Notch target geneswingless and cut, induce ectopic wing margin in adjacent wild-type tissue, inhibit wing-vein formation and have increased levels of Notch intracellular domain immunoreactivity. Clones mutant for bothDelta and hephaestus have the characteristic loss-of-function thick vein phenotype of Delta. These results lead to the hypothesis that hephaestus is required to attenuateNotch activity following its activation by Delta. This is the first genetic analysis of polypyrimidine tract binding protein function in any organism and the first evidence that such proteins may be involved in theNotch signalling pathway.
Anterior-posterior patterning and germ cell specification in Drosophila requires the establishment, during oogenesis, of a specialized cytoplasmic region termed the pole plasm. Numerous RNAs and proteins accumulate to the pole plasm and assemble in polar granules. Translation of some of these RNAs is generally repressed and active only in pole plasm. Vasa (VAS) protein, an RNA helicase and a component of polar granules, is essential maternally for posterior patterning and germ cell specification, and VAS is a candidate translational activator in the pole plasm. VAS is stabilized within the pole plasm in that it is initially present throughout the entire embryo but strictly limited to the pole cells by the cellular blastoderm stage. hsp83 mRNA, which accumulates in the pole plasm through a stabilization-degradation mechanism, is another example. Here, we used a biochemical approach to identify proteins that copurify with VAS in crosslinked extracts. Prominent among these proteins was the ubiquitin-specific protease Fat facets (FAF), a pole plasm component [7], but one whose roles in posterior patterning and germ line specification have remained unclear. We present evidence that FAF interacts with VAS physically and reverses VAS ubiquitination, thereby stabilizing VAS in the pole plasm.
Experiments in cultured cells with Ran-binding protein M (RanBPM) suggest that it links cell surface receptors and cell adhesion proteins. In this study, we undertake a genetic study of RanBPM function in the germline stem cell (GSC) niche of Drosophila melanogaster ovaries. We find that two RanBPM isoforms are produced from alternatively spliced transcripts, the longer of which is specifically enriched in the GSC niche, a cluster of somatic cells that physically anchors GSCs and expresses signals that maintain GSC fate. Loss of the long isoform from the niche causes defects in niche organization and cell size and increases the number of GSCs attached to the niche. In genetic mosaics for a null RanBPM allele, we find a strong bias for GSC attachment to mutant cap cells and observe abnormal accumulation of the adherens junction component Armadillo (β-catenin) and the membrane skeletal protein Hu-li tai shao in mutant terminal filament cells. These results implicate RanBPM in the regulation of niche capacity and adhesion.
The segmentation of the proximal-distal axis of the Drosophila melanogaster leg depends on the localized activation of the Notch receptor. The expression of the Notch ligand genes Serrate and Delta in concentric, segmental rings results in the localized activation of Notch, which induces joint formation and is required for the growth of leg segments. We report here that the expression of Serrate and Delta in the leg is regulated by the transcription factor genes dAP-2 and defective proventriculus. Previous studies have shown that Notch activation induces dAP-2 in cells distal and adjacent to the Serrate/Delta domain of expression. We find that Serrate and Delta are ectopically expressed in dAP-2 mutant legs and that Serrate and Delta are repressed by ectopic expression of dAP-2. Furthermore, Serrate is induced cell-autonomously in dAP-2 mutant clones in many regions of the leg. We also find that the expression of a defective proventriculus reporter overlaps with dAP-2 expression and is complementary to Serrate expression in the tarsal segments. Ectopic expression of defective proventriculus is sufficient to block joint formation and Serrate and Delta expression. Loss of defective proventriculus results in localized, ectopic Serrate expression and the formation of ectopic joints with reversed polarity. Thus, in tarsal segments, dAP-2 and defective proventriculus are necessary for the correct proximal and distal boundaries of Serrate expression and repression of Serrate by defective proventriculus contributes to tarsal segment asymmetry. The repression of the Notch ligand genes Serrate and Delta by the Notch target gene dAP-2 may be a pattern-refining mechanism similar to those acting in embryonic segmentation and compartment boundary formation.
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