scholarly journals Ecdysone signaling promotes expression of multifunctional RNA binding proteins essential for ovarian germline stem cell self-renewal in Drosophila

2018 ◽  
Author(s):  
Danielle S. Finger ◽  
Vivian V. Holt ◽  
Elizabeth T. Ables
Keyword(s):  
Stem Cell ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Bmp Signaling ◽  
Germline Stem Cell ◽  
Self Renewal ◽  
Bmp Receptors ◽  
Morphogenetic Protein ◽  
Ecdysone Signaling

ABSTRACTSteroid hormones promote stem cell self-renewal in many tissues; however, the molecular mechanisms by which hormone signaling is integrated with niche-derived signals are largely uncharacterized. In the Drosophila ovary, the steroid hormone ecdysone promotes germline stem cell (GSC) self-renewal. Despite strong evidence that ecdysone modulates the reception of bone morphogenetic protein (BMP) signals in GSCs, transcriptional targets of ecdysone signaling that facilitate BMP reception are unknown. Here, we report that ecdysone signaling promotes the expression of the heterogeneous nuclear ribonucleoproteins (hnRNPs) squid, hephaestus, Hrb27C, and Hrb87F in GSCs. These hnRNPs functionally interact with ecdysone signaling to control GSC number and are cell autonomously required in GSCs for their maintenance. We demonstrate that hnRNPs promote GSC self-renewal by binding to transcripts essential for proper BMP signaling, including the BMP receptors thickveins and punt. Our findings support the model that stem cells coordinate local and long-range signals at the transcriptional and post-transcriptional levels to maintain self-renewal in response to physiological demand.GRAPHICAL ABSTRACTEcdysone signaling regulates distinct hnRNPs that bind to BMP signaling targets to control GSC self-renewal.SUMMARY STATEMENTEcdysone signaling promotes expression of heterogeneous ribonucleoproteins that modulate BMP-dependent germline stem cell self-renewal in the Drosophila ovary.

scholarly journals Three RNA Binding Proteins Form a Complex to Promote Differentiation of Germline Stem Cell Lineage in Drosophila

PLoS Genetics ◽  
2014 ◽  
Vol 10 (11) ◽  
pp. e1004797 ◽  
Author(s):  
Di Chen ◽  
Chan Wu ◽  
Shaowei Zhao ◽  
Qing Geng ◽  
Yu Gao ◽  
...  
Keyword(s):  
Stem Cell ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Cell Lineage ◽  
Germline Stem Cell ◽  
Stem Cell Lineage

scholarly journals Enforcing Post-Transcriptional Circuitries to Achieve Human Hematopoietic Stem Cell Expansion

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. SCI-46-SCI-46
Author(s):  
Kristin Hope
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Transcriptional Control ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Conflicts Of Interest ◽  
Ex Vivo ◽  
Self Renewal ◽  
Control Of Gene Expression ◽  
Hematopoietic Stem

Abstract The balance between hematopoietic stem cell (HSC) differentiation and self-renewal is central to clinical regenerative paradigms. Unravelling the precise molecular mechanisms that govern HSC fate choices will thus have far reaching consequences for the development of effective therapies for hematopoietic and immunological disorders. There is an emerging recognition that beyond transcription, HSC homeostasis is subject to post-transcriptional control by RNA-binding proteins (RBPs) that ensure precise control of gene expression by modulating mRNA splicing, polyadenylation, localization, degradation or translation. RBPs can synchronously regulate the fates of operationally similar RNAs, in what have been termed RNA regulons. We have used a variety of functional approaches, in combination with unbiased genome- and proteome-scale, methods to define the tenets that govern this regulation and to determine key downstream circuitries of stem cell-regulating RBPs whose targeting could provide the basis for novel regenerative treatments. Through loss-of-function efforts, we have identified the RBP, MSI2, as a required factor for human HSC maintenance. By contrast, at supraphysiological levels, MSI2 has a profound positive effect on human HSC self-renewal decisions. Using a combination of global profiling, including mapping MSI2's targets through cross-linking immunoprecipitation (CLIP)-seq, we show that MSI2 achieves its ex vivo self-renewal-promoting effects by directing a co-ordinated post-transcriptional repression of key targets within the aryl hydrocarbon receptor (AHR) pathway. We are currently exploring the "rules" by which MSI2 influences its downstream effects on target RNAs and how it functions, in combination with other protein interactors, to instill a putative RBP regulatory code in HSCs. HSCs exhibit highly unique epigenomes, transcriptomes and proteomes and it is this distinctive molecular landscape that provides the canvas upon which MSI2, and indeed any other HSC-specific RBP exert their post-transcriptional influence over stem cell function. As such, to decipher the bona fide RNA networks that RBPs function upon in HSCs and to understand how they influence this network to enforce self-renewal, we are working towards performing systematic studies of RBP regulons in these cells specifically. In turn these approaches are elucidating a host of RBPs and post-transcriptional control mechanisms previously unappreciated for their role in HSC control. When modulated appropriately, we can successfully tailor these post-transcriptional regulons to enforce desired HSC outputs ex vivo. In summary, approaches to elucidate key HSC-regulatory RBPs and their protein and RNA interactomes provide valuable insights into a layer of HSC control previously not well understood, and one that can be capitalized on to achieve successful HSC expansion. Disclosures No relevant conflicts of interest to declare.

scholarly journals Functions of Heterogeneous Nuclear Ribonucleoproteins in Stem Cell Potency and Differentiation

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Qishan Chen ◽  
Min Jin ◽  
Jianhua Zhu ◽  
Qingzhong Xiao ◽  
Li Zhang
Keyword(s):  
Gene Expression ◽  
Stem Cell ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Cell Cycle Control ◽  
Nucleic Acid Metabolism ◽  
Specific Gene ◽  
Self Renewal ◽  
Regulatory Pathways ◽  
Heterogeneous Nuclear Ribonucleoproteins

Stem cells possess huge importance in developmental biology, disease modelling, cell replacement therapy, and tissue engineering in regenerative medicine because they have the remarkable potential for self-renewal and to differentiate into almost all the cell types in the human body. Elucidation of molecular mechanisms regulating stem cell potency and differentiation is essential and critical for extensive application. Heterogeneous nuclear ribonucleoproteins (hnRNPs) are modular proteins consisting of RNA-binding motifs and auxiliary domains characterized by extensive and divergent functions in nucleic acid metabolism. Multiple roles of hnRNPs in transcriptional and posttranscriptional regulation enable them to be effective gene expression regulators. More recent findings show that hnRNP proteins are crucial factors implicated in maintenance of stem cell self-renewal and pluripotency and cell differentiation. The hnRNPs interact with certain sequences in target gene promoter regions to initiate transcription. In addition, they recognize 3′UTR or 5′UTR of specific gene mRNA forming mRNP complex to regulate mRNA stability and translation. Both of these regulatory pathways lead to modulation of gene expression that is associated with stem cell proliferation, cell cycle control, pluripotency, and committed differentiation.

scholarly journals The Osa-Containing SWI/SNF Chromatin-Remodeling Complex Is Required in the Germline Differentiation Niche for Germline Stem Cell Progeny Differentiation

Genes ◽  
2021 ◽  
Vol 12 (3) ◽  
pp. 363
Author(s):  
Xiaolong Hu ◽  
Mengjie Li ◽  
Xue Hao ◽  
Yi Lu ◽  
Lei Zhang ◽  
...  
Keyword(s):  
Stem Cell ◽  
Bmp Signaling ◽  
Germline Stem Cell ◽  
Dependent Manner ◽  
Self Renewal ◽  
Cellular Processes ◽  
Lineage Differentiation ◽  
Chromatin Remodeling Complex ◽  
Germline Differentiation ◽  
Drosophila Ovary

The Drosophila ovary is recognized as a powerful model to study stem cell self-renewal and differentiation. Decapentaplegic (Dpp) is secreted from the germline stem cell (GSC) niche to activate Bone Morphogenic Protein (BMP) signaling in GSCs for their self-renewal and is restricted in the differentiation niche for daughter cell differentiation. Here, we report that Switch/sucrose non-fermentable (SWI/SNF) component Osa depletion in escort cells (ECs) results in a blockage of GSC progeny differentiation. Further molecular and genetic analyses suggest that the defective germline differentiation is partially attributed to the elevated dpp transcription in ECs. Moreover, ectopic Engrailed (En) expression in osa-depleted ECs partially contributes to upregulated dpp transcription. Furthermore, we show that Osa regulates germline differentiation in a Brahma (Brm)-associated protein (BAP)-complex-dependent manner. Additionally, the loss of EC long cellular processes upon osa depletion may also partly contribute to the germline differentiation defect. Taken together, these data suggest that the epigenetic factor Osa plays an important role in controlling EC characteristics and germline lineage differentiation.

scholarly journals magu is required for germline stem cell self-renewal through BMP signaling in the Drosophila testis

2011 ◽  
Vol 357 (1) ◽  
pp. 202-210 ◽  
Author(s):  
Qi Zheng ◽  
Yiwen Wang ◽  
Eric Vargas ◽  
Stephen DiNardo
Keyword(s):  
Stem Cell ◽  
Bmp Signaling ◽  
Germline Stem Cell ◽  
Self Renewal ◽  
Drosophila Testis

scholarly journals A PUF hub drives self-renewal in C. elegans germline stem cells

2019 ◽  
Author(s):  
Kimberly A. Haupt ◽  
Kimberley T. Law ◽  
Amy L. Enright ◽  
Charlotte R. Kanzler ◽  
Heaji Shin ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Notch Signaling ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Germline Stem Cells ◽  
Null Mutant ◽  
Self Renewal ◽  
Puf Proteins ◽  
C Elegans

ABSTRACTStem cell regulation relies on extrinsic signaling from a niche plus intrinsic factors that respond and drive self-renewal within stem cells. A priori, loss of niche signaling and loss of the intrinsic self-renewal factors might be expected to have equivalent stem cell defects. Yet this simple prediction has not been borne out for most stem cells, including C. elegans germline stem cells (GSCs). The central regulators of C. elegans GSCs include extrinsically-acting GLP-1/Notch signaling from the niche, intrinsically-acting RNA binding proteins in the PUF family, termed FBF-1 and FBF-2 (collectively FBF), and intrinsically-acting PUF partner proteins that are direct Notch targets. Abrogation of either GLP-1/Notch signaling or its targets yields an earlier and more severe GSC defect than loss of FBF-1 and FBF-2, suggesting that additional intrinsic regulators must exist. Here, we report that those missing regulators are two additional PUF proteins, PUF-3 and PUF-11. Remarkably, an fbf-1 fbf-2; puf-3 puf-11 quadruple null mutant has a GSC defect virtually identical to that of a glp-1/Notch null mutant. PUF-3 and PUF-11 both affect GSC maintenance; both are expressed in GSCs; and epistasis experiments place them at the same position as FBF within the network. Therefore, action of PUF-3 and PUF-11 explains the milder GSC defect in fbf-1 fbf-2 mutants. We conclude that a “PUF hub”, comprising four PUF proteins and two PUF partners, constitutes the intrinsic self-renewal node of the C. elegans GSC RNA regulatory network. Discovery of this hub underscores the significance of PUF RNA-binding proteins as key regulators of stem cell maintenance.

scholarly journals Paracrine Bone Morphogenetic Protein Signaling in Iron Homeostasis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. SCI-26-SCI-26
Author(s):  
Jodie L. Babitt
Keyword(s):  
Iron Deficiency ◽  
Bone Morphogenetic Protein ◽  
Iron Homeostasis ◽  
Molecular Mechanisms ◽  
Bmp Signaling ◽  
Free Oxygen Radicals ◽  
Iron Loading ◽  
Iron Availability ◽  
Bmp Receptors ◽  
Morphogenetic Protein

Iron is an essential nutrient that is required not only for hemoglobin production in red blood cells, but also as a co-factor of many other proteins that perform fundamental cellular processes. However, excess iron can generate free oxygen radicals that can be toxic. Cells and organisms have therefore evolved mechanisms to tightly control iron levels. Systemic iron homeostasis is governed by the iron hormone hepcidin that binds and degrades the iron exporter ferroportin to limit iron absorption from dietary sources and iron release from iron-recycling macrophages and hepatocyte stores. The key source of hepcidin that controls systemic iron homeostasis is the liver. Hepcidin production by the liver is coordinated by several signals that communicate the body's iron needs. Increases in serum and tissue iron induce hepcidin production, whereas iron deficiency suppresses hepcidin production, as feedback mechanisms to maintain steady state iron levels. Inflammation induces hepcidin to limit iron availability to infectious organisms that also require iron to grow and proliferate. Increases in erythropoietic drive suppress hepcidin production to increase iron availability for red blood cell production. The bone morphogenetic protein (BMP) signaling pathway is the central signal transduction pathway that controls hepcidin production in the liver. Activation of BMP signaling by iron loading or suppression of BMP signaling by iron deficiency or erythropoietic drive are key mechanisms by which these signals control hepcidin transcription. Iron loading increases production of BMP6 and BMP2 ligands by liver endothelial cells. Endothelial-derived BMP6 and BMP2 have paracrine actions on BMP receptors and the co-receptor hemojuvelin on hepatocytes to phosphorylate SMAD transcription factors, which translocate to the nucleus to regulate hepcidin transcription. Erythropoietic drive increases the production of erythroferrone by erythrocyte precursors. Erythroferrone is secreted into the circulation where it binds BMP ligands to prevent their interaction with cell surface receptors, thereby inhibiting hepcidin transcription. This talk will focus on recent insights into the molecular mechanisms by whch paracrine BMP signaling in the liver coordinates hepcidin production to regulate systemic iron homeostasis. Disclosures Babitt: Ferrumax Pharmaceuticals, Inc: Equity Ownership, Patents & Royalties; Keryx BIopharmaceuticals, Inc (now part of Akebia Therapeutics): Consultancy; Disc Medicine: Consultancy.

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