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1.
Cell Rep ; 37(2): 109830, 2021 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-34644570

RESUMO

Fat stores are critical for reproductive success and may govern maturation initiation. Here, we report that signaling and sensing fat sufficiency for sexual maturation commitment requires the lipid carrier apolipophorin in fat cells and Sema1a in the neuroendocrine prothoracic gland (PG). Larvae lacking apolpp or Sema1a fail to initiate maturation despite accruing sufficient fat stores, and they continue gaining weight until death. Mechanistically, sensing peripheral body-fat levels via the apolipophorin/Sema1a axis regulates endocytosis, endoplasmic reticulum remodeling, and ribosomal maturation for the acquisition of the PG cells' high biosynthetic and secretory capacity. Downstream of apolipophorin/Sema1a, leptin-like upd2 triggers the cessation of feeding and initiates sexual maturation. Human Leptin in the insect PG substitutes for upd2, preventing obesity and triggering maturation downstream of Sema1a. These data show how peripheral fat levels regulate the control of the maturation decision-making process via remodeling of endomembranes and ribosomal biogenesis in gland cells.


Assuntos
Tecido Adiposo/metabolismo , Adiposidade , Drosophila melanogaster/metabolismo , Glândulas Endócrinas/metabolismo , Ribossomos/metabolismo , Maturidade Sexual , Tecido Adiposo/embriologia , Animais , Animais Geneticamente Modificados , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/embriologia , Drosophila melanogaster/genética , Glândulas Endócrinas/embriologia , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Glicoproteínas/genética , Glicoproteínas/metabolismo , Larva/genética , Larva/metabolismo , Lipogênese , Transporte Proteico , Ribossomos/genética , Semaforinas/genética , Semaforinas/metabolismo , Transdução de Sinais
2.
EMBO J ; 38(21): e101346, 2019 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-31566767

RESUMO

The regenerative activity of adult stem cells carries a risk of cancer, particularly in highly renewable tissues. Members of the family of inhibitor of apoptosis proteins (IAPs) inhibit caspases and cell death, and are often deregulated in adult cancers; however, their roles in normal adult tissue homeostasis are unclear. Here, we show that regulation of the number of enterocyte-committed progenitor (enteroblast) cells in the adult Drosophila involves a caspase-mediated physiological apoptosis, which adaptively eliminates excess enteroblast cells produced by intestinal stem cells (ISCs) and, when blocked, can also lead to tumorigenesis. Importantly, we found that Diap1 is expressed by enteroblast cells and that loss and gain of Diap1 led to changes in enteroblast numbers. We also found that antagonistic interplay between Notch and EGFR signalling governs enteroblast life/death decisions via the Klumpfuss/WT1 and Lozenge/RUNX transcription regulators, which also regulate enteroblast differentiation and cell fate plasticity. These data provide new insights into how caspases drive adult tissue renewal and protect against the formation of tumours.


Assuntos
Apoptose , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/fisiologia , Enterócitos/patologia , Receptores ErbB/metabolismo , Intestinos/patologia , Receptores de Peptídeos de Invertebrados/metabolismo , Receptores Notch/metabolismo , Células-Tronco/patologia , Animais , Caspases , Diferenciação Celular , Linhagem da Célula , Proteínas de Drosophila/genética , Enterócitos/metabolismo , Receptores ErbB/genética , Feminino , Homeostase , Proteínas Inibidoras de Apoptose/genética , Proteínas Inibidoras de Apoptose/metabolismo , Masculino , Receptores de Peptídeos de Invertebrados/genética , Receptores Notch/genética , Transdução de Sinais , Células-Tronco/metabolismo
3.
Cell Rep ; 28(10): 2715-2727.e5, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31484080

RESUMO

Evidence suggests that Polycomb (Pc) is present at chromatin loop anchors in Drosophila. Pc is recruited to DNA through interactions with the GAGA binding factors GAF and Pipsqueak (Psq). Using HiChIP in Drosophila cells, we find that the psq gene, which has diverse roles in development and tumorigenesis, encodes distinct isoforms with unanticipated roles in genome 3D architecture. The BR-C, ttk, and bab domain (BTB)-containing Psq isoform (PsqL) colocalizes genome-wide with known architectural proteins. Conversely, Psq lacking the BTB domain (PsqS) is consistently found at Pc loop anchors and at active enhancers, including those that respond to the hormone ecdysone. After stimulation by this hormone, chromatin 3D organization is altered to connect promoters and ecdysone-responsive enhancers bound by PsqS. Our findings link Psq variants lacking the BTB domain to Pc-bound active enhancers, thus shedding light into their molecular function in chromatin changes underlying the response to hormone stimulus.


Assuntos
Cromatina/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Ecdisona/farmacologia , Elementos Facilitadores Genéticos/genética , Proteínas Nucleares/metabolismo , Complexo Repressor Polycomb 1/metabolismo , Motivos de Aminoácidos , Animais , Linhagem Celular , Proteínas de Drosophila/química , Drosophila melanogaster/efeitos dos fármacos , Proteínas Nucleares/química , Complexo Repressor Polycomb 1/química , Regiões Promotoras Genéticas/genética , Ligação Proteica/efeitos dos fármacos , Domínios Proteicos , Isoformas de Proteínas/metabolismo
4.
Cell Rep ; 22(10): 2541-2549, 2018 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-29514083

RESUMO

The PI3K/Akt signaling pathway, Notch, and other oncogenes cooperate in the induction of aggressive cancers. Elucidating how the PI3K/Akt pathway facilitates tumorigenesis by other oncogenes may offer opportunities to develop drugs with fewer side effects than those currently available. Here, using an unbiased in vivo chemical genetic screen in Drosophila, we identified compounds that inhibit the activity of proinflammatory enzymes nitric oxide synthase (NOS) and lipoxygenase (LOX) as selective suppressors of Notch-PI3K/Akt cooperative oncogenesis. Tumor silencing of NOS and LOX signaling mirrored the antitumor effect of the hit compounds, demonstrating their participation in Notch-PI3K/Akt-induced tumorigenesis. Oncogenic PI3K/Akt signaling triggered inflammation and immunosuppression via aberrant NOS expression. Accordingly, activated Notch tumorigenesis was fueled by hampering the immune response or by NOS overexpression to mimic a protumorigenic environment. Our lead compound, the LOX inhibitor BW B70C, also selectively killed human leukemic cells by dampening the NOTCH1-PI3K/AKT-eNOS axis.


Assuntos
Drosophila melanogaster/metabolismo , Inflamação/patologia , Óxido Nítrico/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Notch/metabolismo , Animais , Carcinogênese/metabolismo , Catecol Oxidase/metabolismo , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Precursores Enzimáticos/metabolismo , Marcação de Genes , Hemócitos/metabolismo , Humanos , Terapia de Imunossupressão , Inflamação/imunologia , Lipoxigenases/metabolismo , Óxido Nítrico Sintase/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Interferência de RNA , Reprodutibilidade dos Testes , Transdução de Sinais
5.
EMBO J ; 34(15): 2025-41, 2015 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-26077448

RESUMO

The intestinal epithelium is remarkably robust despite perturbations and demand uncertainty. Here, we investigate the basis of such robustness using novel tracing methods that allow simultaneously capturing the dynamics of stem and committed progenitor cells (called enteroblasts) and intestinal cell turnover with spatiotemporal resolution. We found that intestinal stem cells (ISCs) divide "ahead" of demand during Drosophila midgut homeostasis. Their newborn enteroblasts, on the other hand, take on a highly polarized shape, acquire invasive properties and motility. They extend long membrane protrusions that make cell-cell contact with mature cells, while exercising a capacity to delay their final differentiation until a local demand materializes. This cellular plasticity is mechanistically linked to the epithelial-mesenchymal transition (EMT) programme mediated by escargot, a snail family gene. Activation of the conserved microRNA miR-8/miR-200 in "pausing" enteroblasts in response to a local cell loss promotes timely terminal differentiation via a reverse MET by antagonizing escargot. Our findings unveil that robust intestinal renewal relies on hitherto unrecognized plasticity in enteroblasts and reveal their active role in sensing and/or responding to local demand.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila/fisiologia , Homeostase/fisiologia , Mucosa Intestinal/fisiologia , MicroRNAs/metabolismo , Células-Tronco/fisiologia , Animais , Sequência de Bases , Sítios de Ligação/genética , Cruzamentos Genéticos , Primers do DNA/genética , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica , Mucosa Intestinal/citologia , Dados de Sequência Molecular , Mutagênese , Interferência de RNA , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sequência de DNA , Imagem com Lapso de Tempo
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