title: The Friend of GATA Transcriptional Co-Regulator, U-Shaped, Is a Downstream Antagonist of Dorsal-Driven Prohemocyte Differentiation in Drosophila.
abstract: Recent studies suggest that mammalian hematopoietic stem and progenitor cells (HSPCs) respond directly to infection and inflammatory signaling. These signaling pathways also regulate HSPCs during steady-state conditions (absence of infection), and dysregulation may lead to cancer or age-related loss of progenitor repopulation capacity. Toll-like receptors (TLRs) are a major class of pathogen recognition receptors, and are expressed on the surface of immune effector cells and HSPCs. TLR/NF-κB activation promotes HSPCs differentiation; however, the mechanisms by which this signaling pathway alters the intrinsic transcriptional landscape are not well understood. Although Drosophila prohemocytes are the functional equivalent of mammalian HSPCs, a prohemocyte-specific function for Toll signaling has not been reported. Using Drosophila transgenics, we identified prohemocyte-specific roles for Toll pathway members, Dorsal and Cactus. We showed that Dorsal is required to limit the size of the progenitor pool. Additionally, we showed that activation of Toll signaling in prohemocytes drives differentiation in a manner that is analogous to TLR/NF-κB-driven HSPC differentiation. This was accomplished by showing that over-expression of Dorsal, or knockdown of Cactus, promotes differentiation. We also investigated whether Dorsal and Cactus control prohemocyte differentiation by regulating a key intrinsic prohemocyte factor, U-shaped (Ush), which is known to promote multipotency and block differentiation. We showed that Dorsal repressed Ush expression levels to promote differentiation, whereas Cactus maintained Ush levels to block differentiation. Additionally, we showed that another Toll antagonist, Lesswright, also maintained the level of Ush to block differentiation and promote proliferative quiescence. Collectively, these results identify a novel role for Ush as a downstream target of Toll signaling.
authors.affiliation: Center for Vascular and Inflammatory Diseases and the Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Hongjuan
authors.initials: H
authors.lastname: Gao
authors.affiliation: Center for Vascular and Inflammatory Diseases and the Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.|Graduate Program in Life Sciences, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Baldeosingh
authors.affiliation: Center for Vascular and Inflammatory Diseases and the Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Wu
authors.affiliation: Center for Vascular and Inflammatory Diseases and the Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.|Graduate Program in Life Sciences, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Nancy
authors.initials: N
authors.lastname: Fossett
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002454:Cell Differentiation; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000276:immunology; D029721:Drosophila Proteins / Q000235:genetics* / Q000276:immunology; D004331:Drosophila melanogaster / Q000235:genetics* / Q000254:growth & development / Q000276:immunology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006410:Hematopoiesis / Q000235:genetics / Q000276:immunology; D006434:Hemocytes / Q000166:cytology / Q000276:immunology*; D007113:Immunity, Innate; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics* / Q000276:immunology; D010750:Phosphoproteins / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000235:genetics* / Q000276:immunology; D014157:Transcription Factors / Q000235:genetics* / Q000276:immunology; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics* / Q000276:immunology; D000098843:Ubiquitin-Conjugating Enzyme UBC9
chemical_list: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D051193:Toll-Like Receptors; D014157:Transcription Factors; C062236:dl protein, Drosophila; C109258:ush protein, Drosophila; C077938:cact protein, Drosophila; D044763:Ubiquitin-Conjugating Enzymes; D000098843:Ubiquitin-Conjugating Enzyme UBC9