Drosophila Ovarian Germline Stem Cell Cytocensor Projections Dynamically Receive and Attenuate BMP Signaling

摘要

class="head no_bottom_margin" id="sec1title">IntroductionThe stem cell niche is a tissue microenvironment, specialized in structure and function, that ensures the self-renewal and survival of cells needed to maintain tissue homeostasis throughout an organism’s life. The first niche was characterized in the Drosophila ovarian germline (, ) where the Bone Morphogenetic Protein (BMP) family member, Decapentaplegic (Dpp), was found to be necessary for maintenance of germline stem cells (GSCs) (, ). Since this discovery, there has been an explosion in the identification and characterization of stem cell niches in most tissues and model organisms ().Within the Drosophila ovary, GSCs are maintained at the anterior tip in discrete structures called germaria (). A small population of somatic cells, the cap cells (CpCs), contact the GSCs through E-cadherin (Ecad)-based adherens junctions (AJs) () and promote stem cell identity through the secretion of Dpp homodimers or Dpp-Glassbottom boat (Gbb) heterodimers. Dpp signals at an exquisitely short range to maintain 2–3 GSCs per niche. Upon cell division, one daughter cell exits the niche, allowing it to move out of the range of the Dpp signal and differentiate into a cystoblast (CB). Multiple mechanisms have been described for restricting Dpp range, including stabilization or concentration of Dpp within the niche by the heparan sulphate proteoglycan (HSPG) Divisions abnormally delayed (Dally), sequestration by a collagen IV (CollIV) matrix between the GSCs and CpCs, and escort cell (EC) expression of the Dpp receptor, Thickveins (Tkv), which acts as a “decoy” to soak up any free BMP ligand (). The most anterior ECs thus define the posterior limit of the GSC niche and contact the differentiating CBs to create a differentiation niche.Within GSCs, the BMP signal is transduced by phosphorylation and activation of the Smad1/5 ortholog, Mothers against Dpp (Mad). Mad oligomerizes with the Smad4 ortholog Medea, leading to their nuclear accumulation (). A key Dpp target gene in GSCs is bag of marbles (bam), encoding an essential differentiation factor, which is repressed by Dpp signaling (, ). Upon cell division, the daughter cell that exits the niche derepresses bam, which initiates the differentiation program. However, few Dpp target genes have been identified in GSCs, and there is little understanding of how the BMP self-renewal signal may positively act on GSC identity. Therefore, we used RNA sequencing (RNA-seq) to identify the GSC transcriptional network, including genes that are regulated by the Dpp signal. These data reveal that the GSC synthesizes different types of cellular projections that function to receive the niche BMP signal, including one class that also plays an active role in BMP signal attenuation, which we thus refer to as “cytocensors.”