The metalloproteinase Papp-aa controls epithelial cell quiescence-proliferation transition

eLife, Journal Year: 2020, Volume and Issue: 9

Published: April 15, 2020

Human patients carrying PAPP‐A2 inactivating mutations have low bone mineral density. The underlying mechanisms for this reduced calcification are poorly understood. Using a zebrafish model, we report that Papp-aa regulates by promoting Ca2+-transporting epithelial cell (ionocyte) quiescence-proliferation transition. Ionocytes, which normally quiescent, re-enter the cycle under [Ca2+] stress. Genetic deletion of Papp-aa, but not closely related Papp-ab, abolished ionocyte proliferation and calcified mass. Loss expression or activity resulted in diminished IGF1 receptor-Akt-Tor signaling ionocytes. Under Ca2+ stress, cleaved Igfbp5a. normal conditions, however, proteinase was suppressed IGFs were sequestered IGF/Igfbp complex. Pharmacological disruption complex adding free activated IGF promoted proliferation. These findings suggest Papp-aa-mediated local Igfbp5a cleavage functions as [Ca2+]-regulated molecular switch linking to stimulating transition

Language: Английский

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Regenerative neurogenic response from glia requires insulin-driven neuron-glia communication

eLife, Journal Year: 2021, Volume and Issue: 10

Published: Feb. 2, 2021

Understanding how injury to the central nervous system induces de novo neurogenesis in animals would help promote regeneration humans. Regenerative could originate from glia and glial neuron-glia antigen-2 (NG2) may sense injury-induced neuronal signals, but these are unknown. Here, we used Drosophila search for genes functionally related NG2 homologue kon-tiki (kon), identified Islet Antigen-2 (Ia-2), required neurons insulin secretion. Both loss over-expression of ia-2 induced neural stem cell gene expression, increased expression ectopic cells. Using genetic analysis lineage tracing, demonstrate that Ia-2 Kon regulate insulin-like peptide 6 (Dilp-6) induce proliferation cells glia. Ectopic can divide, limited be traced back Altogether, Dilp-6 drive a relay restores reprogrammes into regeneration.

Language: Английский

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Msps governs acentrosomal microtubule assembly and reactivation of quiescent neural stem cells

The EMBO Journal, Journal Year: 2021, Volume and Issue: 40(19)

Published: Aug. 9, 2021

The ability of stem cells to switch between quiescence and proliferation is crucial for tissue homeostasis regeneration. Drosophila quiescent neural (NSCs) extend a primary cellular protrusion from the cell body prior their reactivation. However, structure function this are not well established. Here, we show that in NSCs, microtubules predominantly acentrosomal oriented plus-end-out toward tip protrusion. We have identified Mini Spindles (Msps)/XMAP215 as key microtubule regulator NSCs governs NSC reactivation via regulating growth orientation. form membrane contact with neuropil E-cadherin, adhesion molecule, localizes these NSC-neuropil junctions. Msps plus-end directed motor protein Kinesin-2 promote cycle re-entry target E-cadherin during Together, work establishes organization Msps-Kinesin-2 pathway reactivation, part, by targeting E-cad sites.

Language: Английский

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Signaling through the dystrophin glycoprotein complex affects the stress-dependent transcriptome in Drosophila

Disease Models & Mechanisms, Journal Year: 2023, Volume and Issue: 16(1)

Published: Jan. 1, 2023

Deficiencies in the human dystrophin glycoprotein complex (DGC), which links extracellular matrix with intracellular cytoskeleton, cause muscular dystrophies, a group of incurable disorders associated heterogeneous muscle, brain and eye abnormalities. Stresses such as nutrient deprivation aging muscle wasting, can be exacerbated by reduced levels DGC membranes, integrity is vital for health function. Moreover, operates multiple signaling pathways, demonstrating an important function gene expression regulation. To advance disease diagnostics treatment strategies, we strive to understand genetic pathways that are perturbed mutations. Here, utilized Drosophila model investigate transcriptomic changes mutants four components under temperature metabolic stress. We identified DGC-dependent genes, stress-dependent genes dependent on proper stress response, confirming novel stress-response signaling. This perspective yields new insights into etiology dystrophy symptoms, possible directions better understanding regulation normal conditions.

Language: Английский

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Low-Density Lipoproteins Increase Proliferation, Invasion, and Chemoresistance via an Exosome Autocrine Mechanism in MDA-MB-231 Chemoresistant Cells

Biomedicines, Journal Year: 2024, Volume and Issue: 12(4), P. 742 - 742

Published: March 27, 2024

Dyslipidemias involving high concentrations of low-density lipoproteins (LDLs) increase the risk developing triple-negative breast cancer (TNBC), wherein cholesterol metabolism and protein translation initiation mechanisms have been linked with chemoresistance. Doxorubicin (Dox) treatment, a member anthracycline family, represents typical therapeutic strategy; however, chemoresistance remains significant challenge. Exosomes (Exs) secreted by tumoral cells implicated in cell communication pathways mechanisms; content exosomes is an outcome cellular metabolism. We previously induced Dox resistance TNBC models, characterizing variant denominated as B cells. Our results suggest that LDL internalization parental chemoresistant associated increased proliferation, migration, invasion, spheroid growth. identified role eIF4F factor down-regulation tumor suppressor gene PDCD4, inhibitor eIF4A, In addition, exomes were characterized content, electronic microscopy, assays. Critically, purified from LDL-treated promoted increment lactate concentration. autocrine phenomenon may induce modifications on signaling p53/Mdm2 axis activation p70 ribosomal kinase S6. Moreover, specific down-regulated profile chaperones Hsp90 Hsp70 secretion inside could be this phenomenon. Therefore, mediated effect influence changes exosome chaperone modulate proliferative pathways, increasing aggressiveness MDA-MB-231

Language: Английский

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Patronin/CAMSAP promotes reactivation and regeneration of Drosophila quiescent neural stem cells

EMBO Reports, Journal Year: 2023, Volume and Issue: 24(9)

Published: July 13, 2023

The ability of stem cells to switch between quiescent and proliferative states is crucial for maintaining tissue homeostasis regeneration. Drosophila neural (qNSCs) extend a primary protrusion that enriched in acentrosomal microtubules can be regenerated upon injury. Arf1 promotes microtubule growth, reactivation (exit from quiescence), regeneration qNSC protrusions However, how regulated qNSCs remains elusive. Here, we show the minus-end binding protein Patronin/CAMSAP growth NSC reactivation. Patronin important localization at Golgi physically associates with Arf1, preferentially its GDP-bound form. also required protrusion, likely via regulation growth. Finally, functions upstream effector Msps/XMAP215 target cell adhesion molecule E-cadherin NSC-neuropil contact sites during Our findings reveal novel link A similar mechanism might apply various microtubule-dependent systems mammals.

Language: Английский

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Calcium State-Dependent Regulation of Epithelial Cell Quiescence by Stanniocalcin 1a

Frontiers in Cell and Developmental Biology, Journal Year: 2021, Volume and Issue: 9

Published: April 9, 2021

The molecular mechanisms regulating cell quiescence-proliferation balance are not well defined. Using a zebrafish model, we report that Stc1a, secreted glycoprotein, plays key role in the of Ca 2+ transporting epithelial cells (ionocytes). Zebrafish stc1a , but other stc genes, is expressed state-dependent manner. Genetic deletion stc2b increased ionocyte proliferation, leading to elevated body levels, cardiac edema, swelling, and premature death. proliferation was accompanied by an increase IGF1 receptor-mediated PI3 kinase-Akt-Tor signaling activity ionocytes. Inhibition receptor, kinase, Akt, Tor reduced rescued edema death –/– fish, suggesting Stc1a promotes quiescence suppressing local IGF activity. Mechanistically, Stc1 acts inhibiting Papp-aa, zinc metalloproteinase degrading Igfbp5a. Papp-aa proteinase restored balance. papp-aa or its substrate igfbp5a background These findings uncover novel pathway quiescence. Our also provide new insights into importance quiescent-proliferation organismal homeostasis survival.

Language: Английский

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Combining machine learning algorithms and single-cell data to study the pathogenesis of Alzheimer’s disease

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 29, 2024

Abstract Extracting valuable insights from high-throughput biological data of Alzheimer’s disease to enhance understanding its pathogenesis is becoming increasingly important. We engaged in a comprehensive collection and assessment microarray datasets GSE5281 GSE122063 single-cell GSE157827 the NCBI GEO database. The were selected based on stringent screening criteria: P-value less than 0.05 an absolute log fold change (|logFC|) greater 1. Our methodology involved utilizing machine learning algorithms, efficiently identified characteristic genes. This was followed by in-depth immune cell infiltration analysis these genes, gene set enrichment (GSEA) elucidate differential pathways, exploration regulatory networks. Subsequently, we applied Connectivity Map (cMap) approach for drug prediction undertook expression analysis. outcomes revealed that top four their accuracy, exhibited profound correlation with (AD) group terms levels pathways. These genes also showed significant associations multiple AD-related enhancing potential pathogenic mechanisms through network profiling. Identified three subpopulations astrocytes late-stage AD Prefrontal cortex dataset. Discovering dysregulation disease-related pathway maf/nrf2 Ultimately, therapeutic score, offering promising avenues future treatment strategies.

Language: Английский

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SUMOylation of Warts kinase promotes neural stem cell reactivation

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Oct. 17, 2024

Language: Английский

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The Nutrient-Responsive Molecular Chaperone Hsp90 Supports Growth and Development in Drosophila

Frontiers in Physiology, Journal Year: 2021, Volume and Issue: 12

Published: June 22, 2021

Animals can sense internal nutrients, such as amino acids/proteins, and are able to modify their developmental programs in accordance with nutrient status. In the fruit fly, Drosophila melanogaster , acid/protein is sensed by fat body, an insect adipose tissue, through a sensor, target of rapamycin (TOR) complex 1 (TORC1). TORC1 promotes secretion various peptide hormones from body acid/protein-dependent manner. Fat-body-derived stimulate release insulin-like peptides, which essential growth-promoting anabolic hormones, neuroendocrine cells called insulin-producing (IPCs). Although importance body-IPC axis has been elucidated, mechanism regulates expression insulinotropic signal peptides remains unclear. Here, we show that evolutionarily conserved molecular chaperone, heat shock protein 90 (Hsp90), peptides. Fat-body-selective Hsp90 knockdown caused transcriptional downregulation IPC activity systemic growth were also impaired fat-body-selective animals. Furthermore, depended on protein/amino acid availability signaling. These results strongly suggest serves nutrient-responsive gene upregulates growth. We propose induced nutrient-dependent manner support metabolism during juvenile period.

Language: Английский

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