Biology subjects

Zheng, J.

Publications and source records attributed to Zheng, J..

At least 199 records · Page 11Linked to original sources

bioRxiv2023

TREM2 mediates MHCII-associated CD4+ T cell response against gliomas

Triggering receptor expressed on myeloid cells 2 (TREM2) was recently highlighted as a novel immune suppressive marker in peripheral tumors. The aim of this study was to characterize TREM2 expression in gliomas and investigate its contribution in glioma progression by using Trem2-/-mouse line. Our results showed that higher TREM2 expression was correlated with poor prognosis in glioma patients. Unexpectedly, TREM2 deficiency did not have a beneficial effect in a pre-clinical model of glioma. The increased TREM2 expression in glioma was likely due to increased myeloid cell infiltration, as evidenced by our single-cell analysis showing that almost all microglia and macrophages in gliomas were TREM2+. Furthermore, we found that deficiency of TREM2 impaired tumor-myeloid phagocytosis and MHCII presentation, and significantly reduced CD4+ T cells in tumor hemispheres. Our results revealed a previously unrecognized protective role of tumor-myeloid TREM2 in promoting MHCII-associated CD4+ T cell response against gliomas. SUMMARYAuthors found that although higher TREM2 expression is correlated with poor prognosis in glioma patients, its absence has no beneficial effect in a pre-clinical model of glioma. Deficiency of TREM2 impairs myeloid cell phagocytosis of tumor debris, leading to a reduction in MHCII-dependent CD4+ anti-glioma immunity.

neuroscience↗

bioRxiv2023

Homeobox Transcription Factor HbxA Influences Expression of over One ThousandGenes in the Model Fungus Aspergillus nidulans

In fungi, conserved homeobox-domain (HD) proteins are transcriptional regulators governing development. In Aspergillus species, several HD transcription factor genes have been identified, among them, hbxA/hbx1. For instance, in the opportunistic human pathogen Aspergillus fumigatus, hbxA is involved in conidial production and germination, as well as virulence and secondary metabolism (SM), including production of fumigaclavines, fumiquinazolines, and chaetominine. In the agriculturally important fungus Aspergillus flavus, disruption of hbx1 results in fluffy aconidial colonies unable to produce sclerotia. hbx1 also regulates production of aflatoxins, cyclopiazonic acid and aflatrem. Furthermore, transcriptome studies revealed that hbx1 has a broad effect on the A. flavus genome, including numerous genes involved in SM. These studies underline the importance of the HbxA/Hbx1 regulator, not only in developmental processes but also in the biosynthesis of a broad number of fungal natural products, including potential medical drugs and mycotoxins. To gain further insight into the regulatory scope of HbxA in Aspergilli, we studied its role in the model fungus Aspergillus nidulans. Our present study of the A. nidulans hbxA-dependent transcriptome revealed that more than one thousand genes are differentially expressed when this regulator was not transcribed at wild-type levels, among them numerous transcription factors, including those involved in development as well as in SM regulation. Furthermore, our metabolomics analyses revealed that production of several secondary metabolites, some of them associated with A. nidulans hbxA-dependent gene clusters, was also altered in deletion and overexpression hbxA strains compared to the wild type, including synthesis of nidulanins A, B and D, versicolorin A, sterigmatocystin, austinol, dehydroaustinol, and three unknown novel compounds.

genetics↗

bioRxiv2023

MicroRNA-29 Differentially Mediates Preeclampsia-Dysregulated Cellular Responses to Cytokines in Female and Male Fetal Endothelial Cells

IntroductionPreeclampsia (PE) differentially impairs female and male fetal endothelial cell function which is associated with the increased risks of adult-onset cardiovascular disorders in children born to mothers with PE. However, the underlying mechanisms are poorly defined. We hypothesize that dysregulation of microRNA-29a-3p and 29c-3p (miR-29a/c-3p) in PE disturbs gene expression and cellular responses to cytokines in fetal endothelial cells in a fetal sex-dependent manner. MethodsRT-qPCR analysis of miR-29a/c-3p was performed on female and male unpassaged (P0) human umbilical vein endothelial cells (HUVECs) from normotensive (NT) and PE pregnancies. Bioinformatic analysis of an RNAseq dataset was performed to identify PE-dysregulated miR-29a/c-3p target genes in female and male P0-HUVECs. Gain- and loss-of-function assays were conducted to determine the effects of miR-29a/c-3p on endothelial monolayer integrity and proliferation in response to TGF{beta}1 and TNF in NT and PE HUVECs at passage 1. ResultsPE downregulated miR-29a/c-3p in male, but not female P0-HUVECs. PE dysregulated significantly more miR-29a/c-3p target genes in female vs. male P0-HUVECs. Many of these PE-differentially dysregulated miR-29a/c-3p target genes are associated with critical cardiovascular diseases and endothelial functions. We further demonstrated that miR-29a/c-3p knockdown specifically recovered the PE-abolished TGF{beta}1-induced strengthening of endothelial monolayer integrity in female HUVECs, while miR-29a/c-3p overexpression specifically enhanced the TNF-promoted cell proliferation in male PE HUVECs. ConclusionsPE differentially dysregulates miR-29a/c-3p and their target genes associated with cardiovascular diseases- and endothelial function in female and male fetal endothelial cells, possibly contributing to the fetal sex-specific endothelial dysfunction observed in PE.

physiology↗

bioRxiv2023

Long-term reliable neural decoding based on flexible implantable microelectronics and machine learning for seizure prediction application

Neural decoding is useful for understanding brain functions and developing neural interface applications. However, neural interfaces based on rigid electronics often suffer from recording instability due to the foreign body responses caused by their mechanical mismatch with soft tissues, limiting the longitudinal accuracy of neural decoding methods. Herein, it is reported that flexible electronics can be integrated with machine learning algorithms to achieve long-term reliable neural decoding. Wet-spun conductive polymer microfibers showed mechanical robustness and flexibility, low impedance, and chronic biocompatibility, enabling intracerebral neural recordings in epileptic mice at a high signal-to-noise ratio eight weeks after implantation. When the signals recorded by the flexible electrodes were used in machine learning analyses with diverse complex algorithms, they consistently showed higher prediction accuracy for epileptic seizures than stiff metal electrode signals, particularly in the case of using long-term recordings for testing or small-sample datasets for training. A real-time warning system based on the flexible neural electrodes was built that predicted seizures eight minutes in advance with a low false alarm rate. Our work bridges flexible electronics and artificial intelligence for neural decoding applications such as long-term treatment of chronic neurological disorders.

bioengineering↗

bioRxiv2023

Salactin, a dynamically unstable actin homolog in Haloarchaea

Across the domains of life, actin homologs are integral components of many essential processes such as DNA segregation, cell division, and cell shape determination. Archaea genomes, like those of bacteria and eukaryotes, also encode actin homologs, but much less is known about these proteins in vivo dynamics and cellular functions. We identified and characterized the function and dynamics of Salactin, an actin homolog in the hypersaline archaeon Halobacterium salinarum. Despite Salactins homology to bacterial MreB proteins, we find it does not function as a MreB ortholog in H. salinarum. Rather, live-cell imaging revealed that Salactin forms dynamically unstable filaments that grow and shrink out of the cell poles. Like other dynamically unstable polymers, Salactin monomers add at the growing filament end and its ATP-bound critical concentration is substantially lower than the ADP-bound form. When H. salinarums chromosomal copy number becomes limiting under low phosphate growth conditions, cells lacking Salactin show perturbed DNA distributions. Taken together, we propose that Salactin is part of a previously unknown chromosomal segregation apparatus required during low-ploidy conditions.

microbiology↗

bioRxiv2023

Discovery of decreased ferroptosis in male colorectal cancer patients with KRAS mutations

Aberrant tumor metabolism is a hallmark of cancer in which metabolic rewiring can support tumor growth under nutrient deficient conditions. KRAS mutations occur in 35-45% of all colorectal cancer (CRC) cases and are difficult to treat. The relationship between mutant KRAS and aberrant metabolism in CRCs has not been fully explored and could be a target for intervention. We previously acquired non-targeted metabolomics data from 161 tumor tissues and 39 normal colon tissues from stage I-III chemotherapy naive CRC patients. In this study, we revealed that tumors from male patients with KRAS mutations only, had several altered pathways that suppress ferroptosis, including glutathione biosynthesis, transsulfuration activity, and methionine metabolism. To validate this phenotype, MC38 CRC cells (KRASG13R) were treated with a ferroptosis inducer; RAS-selected lethal (RSL3). RSL3 altered metabolic pathways in the opposite direction to that seen in KRAS mutant tumors from male patients confirming a suppressed ferroptosis metabolic phenotype in these patients. We further validated gene expression data from an additional CRC patient cohort (Gene Expression Omnibus (GEO), and similarly observed differences in ferroptosis-related genes by sex and KRAS status. Further examination of the relationship between these genes and overall survival (OS) in the GEO cohort showed that KRAS mutant tumors are associated with poorer 5-year OS compared to KRAS wild type tumors, and only in male patients. Additionally, high compared to low expression of GPX4, FTH1, FTL, which suppressed ferroptosis, were associated with poorer 5-year OS only in KRAS mutant tumors from male CRC patients. Low compared to high expression of ACSL4 was associated with poorer OS for this group. Our results show that KRAS mutant tumors from male CRC patients have suppressed ferroptosis, and gene expression changes that suppress ferroptosis associate with adverse outcomes for these patients, revealing a novel potential avenue for therapeutic approaches.

cancer biology↗

bioRxiv2023

SUMOylation of PTEN promotes DNA end resection through directly dephosphorylating 53BP1 in homologous recombination repair

Homologous recombination (HR) repair for DNA double-strand breaks (DSBs) is critical for maintaining genome stability and cell survival. Nuclear PTEN plays a key role in HR repair, but the underlying mechanism remains largely elusive. We find that SUMOylated PTEN promotes HR repair but represses non-homologous end joining (NHEJ) repair by directly dephosphorylating 53BP1. During DNA damage responses (DDR), p14ARF was phosphorylated and then interacted efficiently with PTEN, thus promoting PTEN SUMOylation as an atypical SUMO E3 ligase. Interestingly, SUMOylated PTEN was subsequently recruited to the chromatin at DNA-break sites. This was because that SUMO1 conjugated to PTEN was recognized and bound by the SUMO-interacting motif (SIM) of BRCA1, which has been located to the core of 53BP1 foci on the chromatin during S/G2 stage. Further, these chromatin-loaded PTEN directly and specifically dephosphorylated pT543 of 53BP1, resulting in the dissociation of 53BP1-complex, which facilitated DNA end resection and ongoing HR repair. The SUMOylation-deficient PTENK254R mice also showed decreased DNA damage repair in vivo. Blocking PTEN SUMOylation pathway with either an SUMOylation inhibitor or a p14ARF(2-13) peptide sensitized tumor cells to chemotherapy. Our study therefore provides the new mechanistic understanding of PTEN in HR repair and clinical intervention of chemo-resistant tumors.

cell biology↗

bioRxiv2023

Chromosome-level genomes of multicellular algal sisters to land plants illuminate signaling network evolution

The filamentous and unicellular algae of the class Zygnematophyceae are the closest algal relatives of land plants. Inferring the properties of the last common ancestor shared by these algae and land plants allows us to identify decisive traits that enabled the conquest of land by plants. We sequenced four genomes of filamentous Zygnematophyceae (three strains of Zygnema circumcarinatum and one strain of Z. cylindricum) and generated chromosome-scale assemblies for all strains of the emerging model system Z. circumcarinatum. Comparative genomic analyses reveal expanded genes for signaling cascades, environmental response, and intracellular trafficking that we associate with multicellularity. Gene family analyses suggest that Zygnematophyceae share all the major enzymes with land plants for cell wall polysaccharide synthesis, degradation, and modifications; most of the enzymes for cell wall innovations, especially for polysaccharide backbone synthesis, were gained more than 700 million years ago. In Zygnematophyceae, these enzyme families expanded, forming co-expressed modules. Transcriptomic profiling of over 19 growth conditions combined with co-expression network analyses uncover cohorts of genes that unite environmental signaling with multicellular developmental programs. Our data shed light on a molecular chassis that balances environmental response and growth modulation across more than 600 million years of streptophyte evolution. HIGHLIGHTSO_LIGenomes of four filamentous algae (Zygnema) sisters to land plants C_LIO_LIZygnema are rich in genes for multicellular growth and environmental acclimation: signaling, lipid modification, and transport C_LIO_LICell wall innovations: diversification of hexameric rosette cellulose synthase in Zygnematophyceae C_LIO_LICo-expression networks reveal conserved modules for balancing growth and acclimation C_LI

evolutionary biology↗

bioRxiv2023

TRPV1 Opening is Stabilized Equally by Its Four Subunits

Capsaicin receptor TRPV1 is a nociceptor for vanilloid molecules such as capsaicin and resiniferatoxin (RTX). Even though cryo-EM structures of TRPV1 in complex with these molecules are available, how their binding energetically favors the open conformation is not known. Here we report an approach to control the number of bound RTX molecules (0-to-4) in functional mouse TRPV1. The approach allowed direct measurements of each of the intermediate open states under equilibrium conditions at both macroscopic and single-molecule levels. We found that RTX binding to each of the four subunits contributes virtually the same activation energy, which we estimated to be 1.86 kcal/mol and found to arise predominately from destabilizing the closed conformation. We further showed that sequential bindings of RTX increase open probability without altering single-channel conductance, confirming that there is likely a single open-pore conformation for TRPV1 activated by RTX.

biophysics↗

bioRxiv2023

USP39 promotes hepatocellular carcinogenesis through regulating alternative splicing in cooperation with SRSF6/HNRNPC

Abnormal alternative splicing (AS) caused by alterations in spliceosomal factors is implicated in cancers. Standard models posit that splice site selection is mainly determined by early spliceosomal U1, U2 snRNPs. Whether and how other mid/late-acting spliceosome components such as USP39 modulate tumorigenic splice site choice remain largely elusive. We observed that hepatocyte-specific knock-in of USP39 promoted hepatocarcinogenesis and potently regulated splice site selection. In human liver cancer cells, USP39 promoted tumor proliferation in a spliceosome-dependent manner. USP39 depletion deregulated hundreds of AS events, including the oncogenic splice-switching of KANK2. Mechanistically, we developed a novel RBP-motif enrichment analysis and found that USP39 modulated exon inclusion/exclusion by interacting with SRSF6/HNRNPC in both humans and mice. Our data represent a paradigm for the control of splice site selection by mid/late-acting spliceosome proteins and their interacting RBPs. USP39 and possibly other mid/late-acting spliceosome proteins may represent potential prognostic biomarkers and targets for cancer therapy. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=97 SRC="FIGDIR/small/525324v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@34cbc1org.highwire.dtl.DTLVardef@2d0ee2org.highwire.dtl.DTLVardef@2c4bd6org.highwire.dtl.DTLVardef@26db00_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2023

The Impact of Species Tree Estimation Error on Cophylogenetic Reconstruction

AO_SCPLOWBSTRACTC_SCPLOWJust as a phylogeny encodes the evolutionary relationships among a group of organisms, a cophylogeny represents the coevolutionary relationships among symbiotic partners. Both are widely used to investigate a range of topics in evolutionary biology and beyond. Both are also primarily reconstructed using computational analysis of biomolecular sequence data as well as other biological character data. The most widely used cophylogenetic reconstruction methods utilize an important simplifying assumption: species phylogenies for each set of coevolved taxa are required as input and assumed to be correct. Many theoretical and experimental studies have shown that this assumption is rarely - if ever - satisfied, and the consequences for cophylogenetic studies are poorly understood. To address this gap, we conduct a comprehensive performance study that quantifies the relationship between species tree estimation error and downstream cophylogenetic estimation accuracy. The study includes performance benchmarking using in silico model-based simulations. Our investigation also includes assessments of cophylogenetic reproducibility using genomic sequence datasets sampled from two important models of symbiosis: soil-associated fungi and their endosymbiotic bacteria, and bobtail squid and their bioluminescent bacterial symbionts. Our findings conclusively demonstrate the major impact that upstream phylogenetic estimation error has on downstream cophylogenetic reconstruction quality.

bioinformatics↗

bioRxiv2022

Lipoprotein sorting to the cell surface via a crosstalk between the Lpt and Lol pathways during outer membrane biogenesis

Lipopolysaccharide (LPS) and lipoprotein, two essential components of the outer membrane (OM) in Gram-negative bacteria, play critical roles in bacterial physiology and pathogenicity. LPS translocation to the OM is mediated by LptDE, yet how lipoproteins sort to the cell surface remains elusive. Here we report the identification of an inventory of lipoproteins that are transported to the cell surface via LptDE. Notably, we determined crystal structures of LptDE from Pseudomonas aeruginosa and its complex with an endogenous Escherichia coli lipoprotein YifL. The paLptDE-YifL structure demonstrates that YifL translocates to the OM via LptDE, in a manner similar to LPS transport. The {beta}-barrel domain serves as a passage for the proteinaceous moiety while its acyl chains are transported outside. Our finding has been corroborated by results from native mass spectrometry, immunofluorescence, and photocrosslinking assays, revealing a unique mechanism through which lipoproteins are translocated across the OM in an ATP- and LPS-dependent manner. Moreover, our study expands the scope of current knowledge of lipoprotein sorting by disclosing a crosstalk between the Lpt and Lol pathways.

microbiology↗

bioRxiv2022

Identification of S1PR4 as an immune modulator for favorable prognosis in HNSCC through unbiased machine learning

As the largest family of membrane proteins, G protein-coupled receptors (GPCRs) are the most prominent family of pharmacological targets. However, only a few GPCRs have been well-defined in terms of their physiological and pathological functions. Thus, an efficient way to identify key GPCRs involved in tumour formation is urgently needed. In this study, patients with head and neck squamous cell carcinoma (HNSCC) were classified into two different subtypes based on the characteristics of GPCRs using an unbiased machine learning method. Notably, these two subtypes showed significant differences in prognosis, gene expression, and immune microenvironment, especially in the infiltration of CD8+ T cells. Based on these differences, we screened three potential key regulators (S1PR4, S1PR5, and GPR87) from all GPCRs and constructed a prognostic nomogram for patients with HNSCC. We identified S1PR4 as the key GPCR in determining the two subtypes for positive correlation with the proportion and cytotoxicity of CD8+ T cells in HNSCC and was mainly expressed in a subset of CX3CR1+CD8+ T cells. We also demonstrated that S1PR4 is an immune modulator for the favourable prognosis of HNSCC patients. We found that S1PR4 was highly expressed in CD8+ T cells from the tumours of HNSCC patients, which was significantly associated with better prognosis, and S1PR4 expression was accompanied by higher T cell cytotoxic marker expression (IFNG and GZMB). Notably, S1PR4 co-localised with CX3CR1, which has been identified as the most cytotoxic marker of CD8+ T cells. Furthermore, S1PR4 upregulation could significantly increase T cell function in CAR-T cell therapy, indicating its great potential in cancer immunotherapy. Therefore, these results identified S1PR4 as a key indicator of cytotoxicity and the proportion of tumour-infiltrating CD8+ T cells and confirmed the prognostic value of S1PR4 in HNSCC. Our findings contribute to the knowledge of S1PR4 in anti-tumour immunity, providing a potential GPCR-targeted therapeutic option for future HNSCC treatment.

cancer biology↗

bioRxiv2022

ClpP/ClpX deficiency impairs mitochondrial functions and mTORC1 signaling during spermatogenesis and meiosis

Caseinolytic protease proteolytic subunit (ClpP) and caseinolytic protease X (ClpX) are mitochondrial matrix peptidases that activate mitochondrial unfolded protein response to maintain protein homeostasis in the mitochondria. However, the role of ClpP and ClpX in spermatogenesis remains largely unknown. In this study, we demonstrated the importance of ClpP/ClpX for meiosis and spermatogenesis with two conditional knockout (cKO) mouse models. We found that ClpP/ClpX deficiency reduced mitochondrial functions and quantity in spermatocytes, affected energy supply during meiosis and attenuated zygotene-pachytene transformation of the male germ cells. The dysregulated spermatocytes finally underwent apoptosis resulting in decreased testicular size and vacuolar structures within the seminiferous tubules. We found mTORC1 pathway was over-activated after deletion of ClpP/ClpX in spermatocytes. Long-term inhibition of the mTORC1 signaling via rapamycin treatment in vivo partially rescue spermatogenesis. The data reveal the novel roles of ClpP and ClpX in regulating meiosis and spermatogenesis. One-Sentence SummaryClpP/ClpX is required for maintaining mitochondrial functions in spermatocytes during meiosis and spermatogenesis.

developmental biology↗

bioRxiv2022

Systematic Approach Identifies Multiple Transcription Factor Perturbations That Rejuvenate Replicatively Aged Human Skin Fibroblasts

Rejuvenation, long a quixotic dream, recently became a possibility through exciting new approaches to counteract aging. For example, parabiosis and partial reprogramming through overexpressing four stem cell transcription factors (Yamanaka factors) both rejuvenate organisms and cells1-5. We hypothesize there are many other genetic solutions to human cell rejuvenation, and some solutions may be safer and more potent than current gene targets. We set out to develop a systematic approach to identify novel genes that, when overexpressed or repressed, reprogram the global gene expression of a cell back to a younger state. Using the Hayflick model of human cell replicative aging, we performed a Perturb-seq screen of 200 transcription factors (TFs) selected through a combination of bioinformatic analysis and literature search. We identified dozens of potentially rejuvenating TFs--those that when overexpressed or repressed in late passage cells reprogrammed global gene expression patterns back to an earlier passage state. We further validated four top TF perturbations through molecular phenotyping of various aging hallmarks. Late passage cells either overexpressing EZH2 or E2F3 or repressing STAT3 or ZFX had more cell division, less senescence, improved proteostasis, and enhanced mitochondrial function. These TF perturbations led to similar downstream gene expression programs. In addition, the rejuvenating effects of these TFs were independent of telomeres. We believe our general approach for identifying rejuvenating factors can be applied to other model systems, and some of the top TF perturbations we discovered will lead to future research in novel, safer rejuvenation therapies.

cell biology↗

bioRxiv2022

Hypothalamic vasopressin sex differentiation is established during embryonic neurogenesis

Arginine vasopressin (AVP) is a conserved sexually dimorphic system regulating behaviors and physiologies. Decades of research concludes that AVP sex differentiation in mice occurs around birth when a gonadal surge of testosterone is converted to estrogen in male sexual dimorphic brain regions. We discovered that AVP neurons in the murine hypothalamus are sexually dimorphic much earlier than this surge, with male mice displaying more AVP neurons than females during neurogenesis at E11. In utero exposure to a pan-ER antagonist blocked AVP masculinization in males, whereas embryonic exogenous 17{beta}-estradiol or xenoestrogen bisphenol A (BPA) masculinized female AVP neurons, causing permanent masculinization effects on adult female AVP cell numbers, projections and intrinsic neuronal properties. Our data reveal that sexual dimorphism of hypothalamic AVP neurons is present from the earliest stages of their differentiation and challenges current dogma that masculinization of the male brain occurs around birth. One-Sentence SummarySexual dimorphism of hypothalamic vasopressin is established during neurogenesis and exposure to the xenoestrogen bisphenol A during pregnancy induces masculinization of female brains

neuroscience↗

bioRxiv2022

Antigen presentation by discrete class I molecules on brain endothelium dynamically regulates T-cell mediated neuropathology in experimental cerebral malaria

CD8 T cell engagement of brain vasculature is a putative mechanism of neuropathology in human cerebral malaria. To define contributions of brain endothelial cell MHC class I antigen-presentation to CD8 T cells in establishing this pathology, we developed novel H-2Kb LoxP and H-2Db LoxP mice crossed with Cdh5-Cre mice to achieve targeted deletion of discrete class I molecules on brain endothelium. Using the Plasmodium berghei ANKA model of experimental cerebral malaria (ECM), we observe that H-2Kb and H-2Db regulate distinct patterns of disease onset, CD8 T cell infiltration, targeted cell death, and regional blood-brain barrier (BBB) disruption. Strikingly, ablation of H-2Kb or H-2Db from brain endothelial cells resulted in reduced CD8 T cell activation, attenuated T cell interaction with brain vasculature, lessened targeted cell death, preserved BBB integrity, and prevented ECM and the death of the animal. These data demonstrate that interactions of CD8 T cells with discrete MHC class I molecules on brain endothelium regulate development of ECM neuropathology. Therefore, targeting MHC class I interactions therapeutically may hold potential for treatment of cases of severe malaria.

neuroscience↗

bioRxiv2022

Intrinsic and extrinsic inhibition of cortical flow underlies symmetry breaking during unilateral cytokinesis

The contractile ring plays crucial roles in animal morphogenesis. Previous studies have explored how tissue mechanics controls the contractile ring; however, the mechanisms by which the ring senses tissue mechanics remain largely unknown. Here, we demonstrate the mechanism of contractile ring mechanosensation and its tuning during asymmetric ring closure of Caenorhabditis elegans embryos. High-resolution imaging of cortical flow revealed that local suppression of the ring-directed cortical flow is associated with a delay in furrowing. This suppression of cortical flow results from cortical compression. We found that the artificial inhibition of ring-directed cortical flow was sufficient to induce asymmetric ring closure in symmetrically dividing cells. Moreover, genetic analysis suggests that the positive feedback loop among ring-directed cortical flow, myosin enrichment, and ring constriction constitutes the anillin-dependent, mechanosensitive engine driving asymmetric ring closure. Our results suggest that the balance between RhoA-dependent and cortical flow-dependent myosin enrichment fine-tunes the rings mechanosensitivity in tissues.

cell biology↗