scholarly journals let-7 coordinates the transition to adulthood through a single primary and four secondary targets

2019 ◽  
Vol 2 (2) ◽  
pp. e201900335 ◽  
Author(s):  
Florian Aeschimann ◽  
Anca Neagu ◽  
Magdalene Rausch ◽  
Helge Großhans
Keyword(s):  
Transition To Adulthood ◽  
Progenitor Cell ◽  
Rna Binding ◽  
Linear Chain ◽  
Transcriptional Regulators ◽  
Cell Fates ◽  
Sexual Organ ◽  
Single Target ◽  
Small Set ◽  
And Function

The juvenile-to-adult (J/A) transition, or puberty, is a period of extensive changes of animal body morphology and function. The onset of puberty is genetically controlled, and the let-7 miRNA temporally regulates J/A transition events in nematodes and mammals. Here, we uncover the targets and downstream pathways through which Caenorhabditis elegans let-7 controls male and female sexual organ morphogenesis and skin progenitor cell fates. We find that let-7 directs all three processes by silencing a single target, the post-transcriptional regulator lin-41. In turn, the RNA-binding protein LIN41/TRIM71 regulates these processes by silencing only four target mRNAs. Thus, by silencing LIN41, let-7 activates LIN-29a and MAB-10 (an early growth response-type transcription factor and its NAB1/2-orthologous cofactor, respectively) to terminate progenitor cell self-renewal and to promote vulval integrity. By contrast, let-7 promotes development of the male sexual organ by up-regulating DMD-3 and MAB-3, two Doublesex/MAB-3 domain–containing transcription factors. Our results provide mechanistic insight into how a linear chain of post-transcriptional regulators diverges in the control of a small set of transcriptional regulators to achieve a coordinated J/A transition.

scholarly journals let-7 controls the transition to adulthood by releasing select transcriptional regulators from repression by LIN41

2018 ◽  
Author(s):  
Florian Aeschimann ◽  
Anca Neagu ◽  
Magdalene Rausch ◽  
Helge Großhans
Keyword(s):  
Transition To Adulthood ◽  
Progenitor Cell ◽  
Temporal Patterning ◽  
Cell Fates ◽  
C Elegans ◽  
Regulatory Module ◽  
Single Target ◽  
Dm Domain ◽  
Multicellular Organisms ◽  
Post Transcriptional Regulation

ABSTRACTDevelopment of multicellular organisms relies on faithful temporal control of cell fates. In Caenorhabditis elegans, the heterochronic pathway governs temporal patterning of somatic cells. This function may be phylogenetically conserved as several heterochronic genes have mammalian orthologues, and as the heterochronic let-7 miRNA and its regulator LIN28 appear to time the onset of puberty in mice and humans. Here, we have investigated how let-7 promotes the transition to adulthood in C. elegans. We find that let-7 controls each of three relevant processes, namely male and female sexual organ morphogenesis as well as changes in skin progenitor cell fates, through the same single target, lin-41. LIN41 in turn silences two pairs of targets post-transcriptionally, by binding and silencing their mRNAs. The EGR-type transcription factor LIN-29a and its co-factor, the NAB1/2 orthologous MAB-10, mediate control of progenitor cell fates and vulval integrity. By contrast, male tail development depends on regulation of the DM domain-containing transcription factors DMD-3 and MAB-3. Our results provide mechanistic insight into an exemplary temporal patterning pathway, demonstrate that let-7 – LIN41 function as a versatile regulatory module that can be connected to different outputs, and reveal how several levels of post-transcriptional regulation ultimately achieve effects through controlling transcriptional outputs.

scholarly journals The RNA binding protein Swm is critical for Drosophila melanogaster intestinal progenitor cell maintenance

2022 ◽  
Author(s):  
Ishara S Ariyapala ◽  
Kasun Buddika ◽  
Heather A Hundley ◽  
Brian Calvi ◽  
Nicholas Sokol
Keyword(s):  
Stem Cell ◽  
Progenitor Cells ◽  
Progenitor Cell ◽  
Transcriptional Control ◽  
Rna Binding ◽  
Rna Binding Protein ◽  
Adult Stem Cell ◽  
Stem Cell Maintenance ◽  
And Function ◽  
Cell Maintenance

The regulation of stem cell survival, self-renewal, and differentiation is critical for the maintenance of tissue homeostasis. Although the involvement of signaling pathways and transcriptional control mechanisms in stem cell regulation have been extensively investigated, the role of post-transcriptional control is still poorly understood. Here we show that the nuclear activity of the RNA-binding protein Second Mitotic Wave Missing (Swm) is critical for Drosophila intestinal stem cells (ISCs) and their daughter cells, enteroblasts (EBs), to maintain their identity and function. Loss of swm in these intestinal progenitor cells leads ISCs and EBs to lose defined cell identities, fail to proliferate, and detach from the basement membrane, resulting in severe progenitor cell loss. swm loss further causes nuclear accumulation of poly(A)+ RNA in progenitor cells. Swm associates with transcripts involved in epithelial cell maintenance and adhesion, and the loss of swm, while not generally affecting the levels of these Swm-bound mRNAs, leads to elevated expression of proteins encoded by some of them, including the fly orthologs of Filamin and Talin. Taken together, this study indicates a role for Swm in adult stem cell maintenance, and raises the possibility that nuclear post-transcriptional gene regulation plays vital roles in controlling adult stem cell maintenance and function.

scholarly journals Analyzing signaling activity and function in hematopoietic cells

2021 ◽  
Vol 218 (7) ◽  
Author(s):  
Tobias Kull ◽  
Timm Schroeder
Keyword(s):  
Cell Signaling ◽  
Signaling Pathways ◽  
Progenitor Cell ◽  
Cell Behavior ◽  
Cell Fates ◽  
Hematopoietic Stem ◽  
Related Individual ◽  
Health And Disease ◽  
And Function ◽  
Signaling Activity

Cells constantly sense their environment, allowing the adaption of cell behavior to changing needs. Fine-tuned responses to complex inputs are computed by signaling pathways, which are wired in complex connected networks. Their activity is highly context-dependent, dynamic, and heterogeneous even between closely related individual cells. Despite lots of progress, our understanding of the precise implementation, relevance, and possible manipulation of cellular signaling in health and disease therefore remains limited. Here, we discuss the requirements, potential, and limitations of the different current technologies for the analysis of hematopoietic stem and progenitor cell signaling and its effect on cell fates.

In Caenorhabditis elegans, the RNA-Binding Domains of the Cytoplasmic Polyadenylation Element Binding Protein FOG-1 Are Needed to Regulate Germ Cell Fates

Genetics ◽  
2001 ◽  
Vol 159 (4) ◽  
pp. 1617-1630
Author(s):  
Suk-Won Jin ◽  
Nancy Arno ◽  
Adam Cohen ◽  
Amy Shah ◽  
Qijin Xu ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Germ Cell ◽  
Rna Binding ◽  
Dominant Negative ◽  
Missense Mutations ◽  
Biochemical Tests ◽  
Cell Fates ◽  
Cytoplasmic Polyadenylation ◽  
Binding Domains ◽  
Rna Binding Domains

Abstract FOG-1 controls germ cell fates in the nematode Caenorhabditis elegans. Sequence analyses revealed that FOG-1 is a cytoplasmic polyadenylation element binding (CPEB) protein; similar proteins from other species have been shown to bind messenger RNAs and regulate their translation. Our analyses of fog-1 mutations indicate that each of the three RNA-binding domains of FOG-1 is essential for activity. In addition, biochemical tests show that FOG-1 is capable of binding RNA sequences in the 3′-untranslated region of its own message. Finally, genetic assays reveal that fog-1 functions zygotically, that the small fog-1 transcript has no detectable function, and that missense mutations in fog-1 cause a dominant negative phenotype. This last observation suggests that FOG-1 acts in a complex, or as a multimer, to regulate translation. On the basis of these data, we propose that FOG-1 binds RNA to regulate germ cell fates and that it does so by controlling the translation of its targets. One of these targets might be the fog-1 transcript itself.

scholarly journals Crystal structure and RNA-binding properties of an Hfq homolog from the deep-branching Aquificae: conservation of the lateral RNA-binding mode

2017 ◽  
Vol 73 (4) ◽  
pp. 294-315 ◽  
Author(s):  
Kimberly A. Stanek ◽  
Jennifer Patterson-West ◽  
Peter S. Randolph ◽  
Cameron Mura
Keyword(s):  
Rna Binding ◽  
Binding Pocket ◽  
Binding Mode ◽  
Evolutionary Conservation ◽  
Aquifex Aeolicus ◽  
Binding Properties ◽  
Bacterial Phyla ◽  
Mrna Targets ◽  
Small Regulatory Rnas ◽  
And Function

The host factor Hfq, as the bacterial branch of the Sm family, is an RNA-binding protein involved in the post-transcriptional regulation of mRNA expression and turnover. Hfq facilitates pairing between small regulatory RNAs (sRNAs) and their corresponding mRNA targets by binding both RNAs and bringing them into close proximity. Hfq homologs self-assemble into homo-hexameric rings with at least two distinct surfaces that bind RNA. Recently, another binding site, dubbed the `lateral rim', has been implicated in sRNA·mRNA annealing; the RNA-binding properties of this site appear to be rather subtle, and its degree of evolutionary conservation is unknown. An Hfq homolog has been identified in the phylogenetically deep-branching thermophileAquifex aeolicus(Aae), but little is known about the structure and function of Hfq from basal bacterial lineages such as the Aquificae. Therefore,AaeHfq was cloned, overexpressed, purified, crystallized and biochemically characterized. Structures ofAaeHfq were determined in space groupsP1 andP6, both to 1.5 Å resolution, and nanomolar-scale binding affinities for uridine- and adenosine-rich RNAs were discovered. Co-crystallization with U6RNA reveals that the outer rim of theAaeHfq hexamer features a well defined binding pocket that is selective for uracil. ThisAaeHfq structure, combined with biochemical and biophysical characterization of the homolog, reveals deep evolutionary conservation of the lateral RNA-binding mode, and lays a foundation for further studies of Hfq-associated RNA biology in ancient bacterial phyla.

scholarly journals Pseudogene ACTBP2 increases blood–brain barrier permeability by promoting KHDRBS2 transcription through recruitment of KMT2D/WDR5 in Aβ1–42 microenvironment

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Qianshuo Liu ◽  
Xiaobai Liu ◽  
Defeng Zhao ◽  
Xuelei Ruan ◽  
Rui Su ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Vital Role ◽  
Brain Barrier ◽  
Blood Brain ◽  
Bbb Permeability ◽  
Novel Target ◽  
And Function

AbstractThe blood–brain barrier (BBB) has a vital role in maintaining the homeostasis of the central nervous system (CNS). Changes in the structure and function of BBB can accelerate Alzheimer’s disease (AD) development. β-Amyloid (Aβ) deposition is the major pathological event of AD. We elucidated the function and possible molecular mechanisms of the effect of pseudogene ACTBP2 on the permeability of BBB in Aβ1–42 microenvironment. BBB model treated with Aβ1–42 for 48 h were used to simulate Aβ-mediated BBB dysfunction in AD. We proved that pseudogene ACTBP2, RNA-binding protein KHDRBS2, and transcription factor HEY2 are highly expressed in ECs that were obtained in a BBB model in vitro in Aβ1–42 microenvironment. In Aβ1–42-incubated ECs, ACTBP2 recruits methyltransferases KMT2D and WDR5, binds to KHDRBS2 promoter, and promotes KHDRBS2 transcription. The interaction of KHDRBS2 with the 3′UTR of HEY2 mRNA increases the stability of HEY2 and promotes its expression. HEY2 increases BBB permeability in Aβ1–42 microenvironment by transcriptionally inhibiting the expression of ZO-1, occludin, and claudin-5. We confirmed that knocking down of Khdrbs2 or Hey2 increased the expression levels of ZO-1, occludin, and claudin-5 in APP/PS1 mice brain microvessels. ACTBP2/KHDRBS2/HEY2 axis has a crucial role in the regulation of BBB permeability in Aβ1–42 microenvironment, which may provide a novel target for the therapy of AD.

Influence fast or later: two types of influencers in social networks

2021 ◽  
Author(s):  
Fang Zhou ◽  
Chang Su ◽  
Shuqi Xu ◽  
Linyuan Lü
Keyword(s):  
Final Stage ◽  
Early Stage ◽  
Large Fraction ◽  
Structure And Function ◽  
Spreading Process ◽  
Spreading Effect ◽  
Local Structures ◽  
Different Types ◽  
Small Set ◽  
And Function

Abstract In real-world networks, there usually exist a small set of nodes that play an important role in the structure and function of networks. Those vital nodes can influence most other nodes in the network via a spreading process. While most of the existing works focused on vital nodes that can maximize the spreading size in the final stage, which we call final influencers, recent work proposed the idea of fast influencers, which emphasizes nodes’ spreading capacity at the early stage. Despite the recent surge of efforts in identifying these two types of influencers in networks, there remained limited research on untangling the differences between fast influencers and final influencers. In this paper, we first distinguish the two types of influencers: fast-only influencers and final-only influencers. The former is defined as individuals who can achieve a high spreading effect at the early stage but lose their superiority in the final stage, and the latter are those individuals that fail to exhibit a prominent spreading performance at the early stage but influence a large fraction of nodes at the final stage. Further experiments based on eight empirical datasets, we reveal the key differences between the two types of influencers concerning their spreading capacity and the local structures. We also analyze how network degree assortativity influences the fraction of the proposed two types of influencers. The results demonstrate that with the increase of degree assortativity, the fraction of the fast-only influencers decreases, which indicates that more fast influencers tend to keep their superiority at the final stage. Our study provides insights into the differences and evolution of different types of influencers and has important implications for various empirical applications, such as advertisement marketing, and epidemic suppressing.

scholarly journals The control of inflammation via the phosphorylation and dephosphorylation of tristetraprolin: a tale of two phosphatases

2016 ◽  
Vol 44 (5) ◽  
pp. 1321-1337 ◽  
Author(s):  
Andrew R. Clark ◽  
Jonathan L.E. Dean
Keyword(s):  
Inflammatory Mediators ◽  
Knockout Mouse ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Human Orthologue ◽  
And Function ◽  
Detailed Picture ◽  
Lines Of Evidence

Twenty years ago, the first description of a tristetraprolin (TTP) knockout mouse highlighted the fundamental role of TTP in the restraint of inflammation. Since then, work from several groups has generated a detailed picture of the expression and function of TTP. It is a sequence-specific RNA-binding protein that orchestrates the deadenylation and degradation of several mRNAs encoding inflammatory mediators. It is very extensively post-translationally modified, with more than 30 phosphorylations that are supported by at least two independent lines of evidence. The phosphorylation of two particular residues, serines 52 and 178 of mouse TTP (serines 60 and 186 of the human orthologue), has profound effects on the expression, function and localisation of TTP. Here, we discuss the control of TTP biology via its phosphorylation and dephosphorylation, with a particular focus on recent advances and on questions that remain unanswered.

scholarly journals The Putative RNA-Binding Protein Nrp1 Promotes the Loading of Kinesin-14/Klp2 to the Mitotic Spindle and Is Sequestered Into Heat-Induced Protein Aggregates in Fission Yeast

2021 ◽  
Author(s):  
Masashi Yukawa ◽  
Mitsuki Ohishi ◽  
Yusuke Yamada ◽  
Takashi Toda
Keyword(s):  
Fission Yeast ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Protein Aggregates ◽  
Associated Proteins ◽  
Spindle Microtubules ◽  
The Stability ◽  
And Function ◽  
Post Transcriptional Regulation

Cells form a bipolar spindle during mitosis to ensure accurate chromosome segregation. Proper spindle architecture is established by a set of kinesin motors and microtubule-associated proteins. In most eukaryotes, kinesin-5 motors are essential for this process, and genetic or chemical inhibition of their activity leads to the emergence of monopolar spindles and cell death. However, these deficiencies can be rescued by simultaneous inactivation of kinesin-14 motors, as they counteract kinesin-5. We conducted detailed genetic analyses in fission yeast to understand the mechanisms driving spindle assembly in the absence of kinesin-5. Here we show that deletion of the nrp1 gene, which encodes a putative RNA-binding protein with unknown function, can rescue temperature sensitivity caused by cut7-22, a fission yeast kinesin-5 mutant. Interestingly, kinesin-14/Klp2 levels on the spindles in the cut7 mutants were significantly reduced by the nrp1 deletion, although the total levels of Klp2 and the stability of spindle microtubules remained unaffected. Moreover, RNA-binding motifs of Nrp1 are essential for its cytoplasmic localization and function. We have also found that a portion of Nrp1 is spatially and functionally sequestered by chaperone-based protein aggregates upon mild heat stress and limits cell division at high temperatures. We propose that Nrp1 might be involved in post-transcriptional regulation through its RNA-binding ability to promote the loading of Klp2 on the spindle microtubules.

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