Biology subjects

Chang, L.

Publications and source records attributed to Chang, L..

At least 55 records · Page 3Linked to original sources

bioRxiv2024

Delicate tuning of H2O2 by salicylic acid, catalase 2, and AtSAP5 incites plant immunity

Salicylic acid (SA) triggers plant immunity through redox state changes, initially oxidizing and then reducing. SA binds and inhibits the H2O2-scavenging enzyme catalase 2 (CAT2), promoting an initial oxidative state. However, a reduced state is crucial for a robust immune response. In Arabidopsis, the SA-induced A20/AN1 zinc finger protein, AtSAP5, competes with SA for CAT2 binding, maintaining CAT2 activity. This reduces H2O2 levels and prevents CAT2 degradation through inhibition of H2O2-induced autophagy formation, which forms a positive feedback loop to CAT2 accumulation. Consequently, cells shift to a more reduced state, activating immune responses. Our findings reveal a nuanced regulatory mechanism through which H2O2 levels are controlled by SA with cross-kingdom conserved proteins AtSAP5 and CAT2, managing redox states and plant immunity.

plant biology↗

bioRxiv2024

Identification of potent biparatopic antibodies targeting FGFR2 fusion driven cholangiocarcinoma.

Translocations involving FGFR2 gene fusions are common in cholangiocarcinoma and predict response to FGFR kinase inhibitors. However, the rate and durability of response are limited due to the emergence of resistance, typically involving acquired FGFR2 kinase domain mutations, and to sub-optimal dosing, relating to drug adverse effects. Here, we report the development of biparatopic antibodies targeting the FGFR2 extracellular domain (ECD), as candidate therapeutics. Biparatopic antibodies can overcome drawbacks of standard bivalent monoparatopic antibodies, which often show poor inhibitory or even agonist activity against oncogenic receptors. We show that oncogenic transformation by FGFR2 fusions requires an intact ECD. Moreover, by systematically generating biparatopic antibodies that target distinct epitope pairs along the FGFR2 ECD, we identified antibodies that effectively block signaling and malignant growth driven by FGFR2-fusions. Importantly, these antibodies demonstrate efficacy in vivo, synergy with FGFR inhibitors, and activity against FGFR2 fusions harboring kinase domain mutations. Thus, biparatopic antibodies may serve as new treatment options for patients with FGFR2-altered cholangiocarcinoma. SummaryWe identify biparatopic FGFR2 antibodies that are effective against FGFR2 fusion driven cholangiocarcinoma.

cancer biology↗

bioRxiv2024

Intracortical injection of immune checkpoint inhibitor promotes monocyte/macrophage infiltration and restores microglial function and neuronal activity in an AD mouse model

Alzheimer's disease (AD) involves complex neuroimmune interactions. However, the role of immune checkpoint pathways in regulating the glial and neuronal functions of the AD brain remains unclear. This study aims to investigate how the brain-specific modulation of the PD-1/PD-L1 axis affects glial and neuronal function in an AD mouse model, which is characterized by the significant upregulation of microglial PD-1 and astrocytic PD-L1. A single intracortical administration of anti-PD-L1 antibody reshaped the glial microenvironment, which was accompanied by the restoration of impaired microglial process convergence. Astrocyte-specific Pd-l1 knockdown using the pSico system validated the essential role of astrocytic PD-L1 in enhancing microglial responses. Notably, the blockade of the PD-1/PD-L1 signaling pathway increased the microglial P2RY12 expression, a key marker of microglial homeostasis, which likely contributed to the restoration of neuronal hyperactivity. Collectively, these findings confirmed the potential of targeting the astrocyte-microglia PD-1/PD-L1 axis to mitigate AD pathology.

neuroscience↗

bioRxiv2024

AlphaFold2 knows some protein folding principles

AlphaFold2 (AF2) has revolutionized protein structure prediction. However, a common confusion lies in equating the protein structure prediction problem with the protein folding problem. The former provides a static structure, while the latter explains the dynamic folding pathway to that structure. We challenge the current status quo and advocate that AF2 has indeed learned some protein folding prin- ciples, despite being designed for structure prediction. AF2s high-dimensional parameters encode an imperfect biophysical scoring function. Typically, AF2 uses multiple sequence alignments (MSAs) to guide the search within a narrow re- gion of its learned surface. In our study, we operate AF2 without MSAs or initial templates, forcing it to sample its entire energy landscape -- more akin to an ab initio approach. Among over 7,000 proteins, a fraction fold using sequence alone, highlighting the smoothness of AF2s learned energy surface. Additionally, by combining recycling and iterative predictions, we discover multiple AF2 interme- diate structures in good agreement with known experimental data. AF2 appears to follow a "local first, global later" folding mechanism. For designed proteins with more optimized local interactions, AF2s energy landscape is too smooth to detect intermediates even when it should. Our current work sheds new light on what AF2 has learned and opens exciting possibilities to advance our understanding of protein folding and for experimental discovery of folding intermediates.

biophysics↗

bioRxiv2024

ER stress-induced TREM2 downregulation exacerbates platelet activation and myocardial infarction in patients with coronary artery disease

Coronary artery disease (CAD) is characterized by the chronic immune-inflammation, excessive endoplasmic reticulum (ER) stress, and platelet hyperactivity; however, whether there is a signaling hub linking these events remains unclear. Here, we identified that triggering receptor expressed on myeloid cells 2 (TREM2), an important pattern recognition receptor of the innate immune system, may serve as one such hub. We found that platelets expressed TREM2 and platelets from CAD patients had decreased TREM2 expression compared to healthy subjects. Decreased TREM2 is associated with platelet hyperactivity in CAD patients. This decrease could be due to excessive ER stress, which downregulated TREM2 through the CHOP-C/EBP axis. Loss of TREM2 not only enhanced platelet activation in response to ADP, collagen, and collagen-related peptide (CRP), but also amplified the platelet inflammatory response. Loss of TREM2 exacerbated mouse mesenteric arterial thrombosis and aggravated experimental myocardial infarction (MI). Moreover, a TREM2-activating antibody inhibited platelet activation, alleviated arterial thrombosis and pulmonary embolism. In addition, TREM2-activating antibody exhibited cardioprotective roles against experimental MI and reduced the inflammatory burden. Mechanistically, TREM2/DAP12/SHIP1 axis negatively regulated platelet activation through reducing PIP3 levels and inhibiting Akt phosphorylation. We also provided evidence supporting sphingosine-1-phospage (S1P) as a physiological agonist of TREM2. In summary, we find that TREM2 connects chronic immune-inflammation, excessive ER stress, and platelet hyperactivity in CAD patients. Downregulating TREM2 by ER stress exacerbates platelet activation and amplifies inflammation response in patients with CAD. TREM2-activating antibodies may have therapeutic potential for CAD patients. Key PointsO_LIPlatelets from CAD patients have decreased TREM2 expression, which is caused by ER stress and associated with platelet hyperactivity. C_LIO_LIS1P-TREM2-SHIP1 pathway inhibits platelet activation, alleviates arterial thrombosis, and exhibits cardioprotective roles against experimental myocardial infarction. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=88 SRC="FIGDIR/small/608887v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@1e21f2eorg.highwire.dtl.DTLVardef@6d427forg.highwire.dtl.DTLVardef@128af74org.highwire.dtl.DTLVardef@16f48c_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOVisual Abstract.C_FLOATNO Downregulation of platelet TREM2 caused by ER stress in CAD patients leads to platelet hyperactivity and aggravates myocardial ischemia, which is rescued by TREM2-activating antibody. Excessive ER stress in CAD upregulates CHOP, which dimerizes with C/EBP, a transcription factor of TREM2, decreases TREM2 transcription and expression in megakaryocytes and further in platelets. TREM2/DAP12/SHIP1/Akt pathway negatively regulates platelet activation; decreased TREM2 thus aggravates platelet hyperactivity, inflammation, and myocardial infarction, which can be rescued by TREM2 activation including antibody or the small molecule agonist. Physiologically, S1P released from platelet granules is an endogenous agonist of TREM2. C_FIG

pharmacology and toxicology↗

bioRxiv2024

Calcium tunneling through the entoplasmic reticulum and transfer to other organelles for optimal signaling in Toxoplasma gondii

Ca2+ signaling in cells begins with the opening of Ca2+ channels in either the plasma membrane (PM) or endoplasmic reticulum (ER), leading to a sharp increase of the physiologically low (<100 nM) cytosolic Ca2+ level. The temporal and spatial regulation of Ca{superscript 2} is crucial for the precise activation of key biological processes. In the apicomplexan parasite Toxoplasma gondii, which infects approximately one-third of the global population, Ca{superscript 2} signaling governs essential aspects of the parasites infection cycle. T. gondii relies on Ca{superscript 2} signals to regulate pathogenic traits, with several Ca{superscript 2}-signaling components playing critical roles. Ca2+ entry from the extracellular environment has been demonstrated in T. gondii for both, extracellular parasites, exposed to high Ca2+, and intracellular parasites, which acquire Ca{superscript 2} from host cells during host Ca{superscript 2} signaling events. Active egress, an essential step of the parasites infection cycle, is preceded by a large increase in cytosolic Ca2+, most likely initiated by release from intracellular stores. However, extracellular Ca2+ is also necessary to reach a cytosolic Ca2+ threshold required for timely egress. In this study, we investigated the mechanism of Ca{superscript 2} intracellular store replenishment and identified a central role for the SERCA-Ca2+-ATPase in maintaining Ca{superscript 2} homeostasis not only within the ER but also in other organelles. We demonstrate mitochondrial Ca2+ uptake, which occurs by transfer of Ca2+ from the ER, likely through membrane contact sites. Our findings suggest that the T. gondii ER plays a key role in sequestering and redistributing Ca{superscript 2} to intracellular organelles following Ca{superscript 2} influx at the PM. HIGHLIGHTSThe T. gondii ER takes up Ca2+ that enters the cytosol from the extracellular milieu. Filling of acidic stores in T. gondii depends on ER Ca{superscript 2} content. The mitochondrion of T. gondii has no direct access to extracellular Ca{superscript 2} but can take it up via transfer from the ER and/or acidic stores. The absence of SERCA activity results in reduced Ca{superscript 2} levels in the ER as well as in other organelles

cell biology↗

bioRxiv2024

Mass spectrometric profiling of estrogen and estrogen metabolites in human stool and plasma partially elucidates the role of the gut microbiome in estrogen recycling

Estrogen and estrogen metabolites are commonly measured in human plasma and serum, but there exist almost no reports of estrogen measured in human stool. This methodological limitation in turn limits our understanding of the relationship between systemic and intestinal estrogen. We thus developed a highly sensitive liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) method for measuring free and conjugated forms of 15 estrogens and estrogen metabolites in human stool and plasma. We first investigated human stool and plasma estrogen in healthy control males; follicular and luteal phase premenopausal females; and postmenopausal females. Most estrogens were present in the plasma and stool of all groups, and plasma estrogen levels correlated with stool estrogen levels. In stool, estrogens were higher in premenopausal females, with estrogen levels rising across the menstrual cycle. We further combined these measures with shotgun metagenomic sequencing of the stool microbiomes. The level of estrogen deconjugation enzyme gene copy number (beta-glucuronidase + arylsulfatase) was higher in premenopausal females; while the gene copy numbers of beta-glucuronidase + arylsulfatase, but not beta-glucuronidase alone, correlated with reactivated stool estrogen in all groups. Moreover, deconjugation enzyme gene copy number correlated with plasma total estrogen in males and with individual plasma estrogen metabolites in all groups. These results support the hypothesis that gut microbial beta-glucuronidase and arylsulfatase control the reactivation of gut estrogen while modulating systemic levels through the uptake and recirculation of reactivated estrogen.

molecular biology↗

bioRxiv2024

Size evolution of gigantic genomes suggests stochastic outcomes of transposable element/host silencing interactions

Size evolution among gigantic genomes involves gain and loss of many gigabases of transposable elements (TEs), sequences that parasitize host genomes. Animals suppress TEs using piRNA and KRAB-ZFP pathways. TEs and hosts coevolve in an arms race, where suppression strength reflects TE fitness costs. In enormous genomes, additional TE costs become miniscule. How, then, do TEs and host suppression invoke further addition of massive DNA amounts? We analyzed TE proliferation histories, deletion rates, and community diversities in six salamander genomes (21.3 - 49.9 Gb), alongside gonadal expression of TEs and suppression pathways. TE activity is higher in testes than ovaries, attributable to lower KRAB-ZFP suppression. Unexpectedly, genome size/expansion is uncorrelated with TE deletion rate, proliferation history, expression, and host suppression. Also, TE community diversity increases with genome size, contrasting theoretical predictions. TE/host antagonism in gigantic genomes likely produces stochastic TE accumulation, determined by noisy intermolecular interactions in huge genomes/cells.

evolutionary biology↗

bioRxiv2024

TrkA+ sensory neurons regulate osteosarcoma proliferation and vascularization to promote disease progression

Bone pain is a presenting feature of bone cancers such as osteosarcoma (OS), relayed by skeletal-innervating peripheral afferent neurons. Potential functions of tumor-associated sensory neurons in bone cancers beyond pain sensation are unknown. To uncover neural regulatory functions, a chemical-genetic approach in mice with a knock-in allele for TrkA was used to functionally perturb sensory nerve innervation during OS growth and disease progression. TrkA inhibition in transgenic mice led to significant reductions in sarcoma-associated sensory innervation and vascularization, tumor growth and metastasis, and prolonged overall survival. Single-cell transcriptomics revealed that sarcoma denervation was associated with phenotypic alterations in both OS tumor cells and cells within the tumor microenvironment, and with reduced calcitonin gene-related peptide (CGRP) and vascular endothelial growth factor (VEGF) signaling. Multimodal and multi-omics analyses of human OS bone samples and human dorsal root ganglia neurons further implicated peripheral innervation and neurotrophin signaling in OS tumor biology. In order to curb tumor-associated axonal ingrowth, we next leveraged FDA-approved bupivacaine liposomes leading to significant reductions in sarcoma growth, vascularity, as well as alleviation of pain. In sum, TrkA-expressing peripheral neurons positively regulate key aspects of OS progression and sensory neural inhibition appears to disrupt calcitonin receptor signaling (CALCR) and VEGF signaling within the sarcoma microenvironment leading to significantly reduced tumor growth and improved survival. These data suggest that interventions to prevent pathological innervation of osteosarcoma represent a novel adjunctive therapy to improve clinical outcomes and survival.

cancer biology↗

bioRxiv2024

Chemically induced cell plasticity enables the generation of high-fidelity embryo model

Embryo models open exciting opportunities for improving our understanding of development and advancing medicine. However, current models depend on intricate procedures and the integration of separately generated cell types. Here, we aimed to establish a chemical-only strategy to induce cellular plasticity and generate embryo founder-like cells. Within 60 hours, chemical-induced pluripotent stem cells activated early lineage specifiers, Cdx2 and Gata6, while maintaining Oct4/ Pou5f1 expression. Following a second 36-hour chemical treatment, founder-like cells developed into all blastocyst fates and self-assembled into embryo-like structures. These progressed into high-fidelity late-streak gastrulation stages within 4.5 days, displaying primitive streak formation via epithelial-to-mesenchymal transition, along with germ-layer tissues, amnion, and ectoplacental cone. Fate trajectories and molecular signatures from founder-like cells to chemically-induced embryo model (ci-MO) were defined, revealing remarkable similarity up to Embryonic day (E) 7.5 embryo. Summarily, ci-MO offers a straightforward, rapid, small-molecule-only, and high-fidelity approach to study embryonic development and cell fate specification. HighlightsO_LIGeneration of a direct, efficient, and sophisticated chemically induced embryo model (ci-MO) C_LIO_LITwo-pulse chemical induction reprograms ESCs into founder-like cells capable of developing all embryo fates C_LIO_LIGastrulating ci-MOs display high morphological and molecular accuracy C_LIO_LIci-MOs reconstruct embryo developmental trajectories C_LI

cell biology↗

bioRxiv2024

Patch and matrix striatonigral neurons differentially regulate locomotion

Spiny projection neurons (SPNs) in the dorsal striatum play crucial roles in locomotion control and value-based decision-making. SPNs, which include both direct-pathway striatonigral and indirect-pathway striatopallidal neurons, can be further classified into subtypes based on distinct transcriptomic profiles and cell body distribution patterns. However, how these SPN subtypes regulate spontaneous locomotion in the context of environmental valence remains unclear. Using Sepw1-Cre transgenic mice, which label a specific SPN subtype characterized by a patchy distribution of cell bodies in the dorsal striatum, we found that these patchy striatonigral neurons constrain motor vigor in response to valence differentials. In a modified light/dark box test, mice exhibited differential walking speeds between the light and dark zones. Genetic ablation of these patchy SPNs disrupted restful slowing in the dark zone and increased zone discrimination by speed. In vivo recordings linked the activity of these neurons to zone occupancy, speed, and deceleration, with a specific role in mediating deceleration. Furthermore, chemogenetic activation of patchy SPNs--and optical activation of striatonigral neurons in particular--reduced locomotion and attenuated speed-based zone discrimination. These findings reveal that a subtype of patchy striatonigral neurons regulates implicit walking speed selection based on innate valence differentials.

neuroscience↗

bioRxiv2024

Droplet Hi-C for Fast and Scalable Profiling of Chromatin Architecture in Single Cells

Comprehensive analysis of chromatin architecture is crucial for understanding the gene regulatory programs during development and in disease pathogenesis, yet current methods often inadequately address the unique challenges presented by analysis of heterogeneous tissue samples. Here, we introduce Droplet Hi-C, which employs a commercial microfluidic device for high-throughput, single-cell chromatin conformation profiling in droplets. Using Droplet Hi-C, we mapped the chromatin architecture at single-cell resolution from the mouse cortex and analyzed gene regulatory programs in major cortical cell types. Additionally, we used this technique to detect copy number variation (CNV), structural variations (SVs) and extrachromosomal DNA (ecDNA) in cancer cells, revealing clonal dynamics and other oncogenic events during treatment. We further refined this technique to allow for joint profiling of chromatin architecture and transcriptome in single cells, facilitating a more comprehensive exploration of the links between chromatin architecture and gene expression in both normal tissues and tumors. Thus, Droplet Hi-C not only addresses critical gaps in chromatin analysis of heterogeneous tissues but also emerges as a versatile tool enhancing our understanding of gene regulation in health and disease.

genomics↗

bioRxiv2024

Identification of Aggregation Pheromone in Odontothrips loti (Thysanoptera: Thripidae)

Pheromone trapping is an interspecific, active at low concentrations, eco-friendly pest management strategy that has been widely used for population monitoring. Pheromones have only been validated for a few species in Thysanoptera and the pheromone components of Odontothrips loti Haliday are still unclear. In our study, we have identified (R)-lavandulyl (R)-2-methylbutanoate from male O. loti headspace volatiles by gas chromatography-mass spectrometry (GC-MS), which was structurally similar to the known reported aggregation pheromone of Megalurothrips sjostedti. Y-tube olfactometer assays showed that both male and female adults O. loti were significantly attracted by synthetic (R)-lavandulyl (R)-2-methylbutyrate, implicating as an aggregation pheromone. Additionally, electroantennogram responses of O. loti increased with increasing doses of synthetic (R)-lavandulyl (R)-2-methylbutyrate. This is the first report of a male-produced aggregation pheromone in O. loti, from genus Odontothrips. The discovery of aggregation pheromone of O. loti as a primary pest of alfalfa will provide the possibility of monitoring and early warning in alfalfa grass fields and is expected to be used for integrated management for O. loti.

ecology↗

bioRxiv2023

Multidimensional neural representations of social features during movie viewing

The social world is dynamic and contextually embedded. Yet, most studies utilize simple stimuli that do not capture the complexity of everyday social episodes. To address this, we implemented a movie viewing paradigm and investigated how the everyday social episodes are processed in the brain. Participants watched one of two movies during an MRI scan. Neural patterns from brain regions involved in social perception, mentalization, action observation, and sensory processing were extracted. Representational similarity analysis results revealed that several labeled social features (including social interaction, mentalization, the actions of others, characters talking about themselves, talking about others, and talking about objects) were represented in superior temporal gyrus (STG) and middle temporal gyrus (MTG). The mentalization feature was also represented throughout the theory of mind network, and characters talking about others engaged the temporoparietal junction (TPJ), suggesting that listeners may spontaneously infer the mental state of those being talked about. In contrast, we did not observe the action representations in frontoparietal regions of the action observation network. The current findings indicate that STG and MTG serve as central hubs for social processing, and that listening to characters talk about others elicits spontaneous mental state inference in TPJ during natural movie viewing.

neuroscience↗

bioRxiv2023

Harnessing the endogenous Type I-C CRISPR-Cas system for genome editing in Bifidobacterium breve

Bifidobacterium breve, one of the main bifidobacterial species colonizing the human gastrointestinal tract in early life, has received extensive attention for its purported beneficial effects on human health. However, exploration of the mode of action of such beneficial effects exerted by B. breve is cumbersome due to the lack of effective genetic tools, which limits its synthetic biology application. Given the widespread presence of endogenous CRISPR-Cas systems in B. breve, the current study developed an endogenous CRISPR-based gene editing toolkit for genetic manipulation of B. breve. Deletion of the gene coding uracil phosphoribosyl-transferase (upp) was achieved in two different B. breve strains using this system. In addition, translational termination of uracil phosphoribosyl-transferase was successfully achieved in B. breve FJSWX38M7 by single-base substitution of the upp gene and insertion of three stop codons. The gene encoding linoleic acid isomerase (bbi) in B. breve, being a characteristic trait, was deleted after plasmid curing, which rendered it unable to convert linoleic acid into conjugated linoleic acid, demonstrating the feasibility of successive editing. This study expanded the gene manipulation toolkit of B. breve and provides a reference for functional genome editing and analysis using an endogenous CRISPR-Cas system in Bifidobacterium. ImportanceThe lack of effective genetic tools for Bifidobacterium breve is an obstacle to studying the molecular mechanisms of its health-promoting effects, hindering the development of next-generation probiotics. Here, we introduce a gene editing method based on the endogenous CRISPR-Cas system, which can achieve gene deletion, single base substitution, gene insertion and continuous gene editing in B. breve. This study will promote the excavation of functional genes and elucidation of molecular mechanisms of B. breve.

molecular biology↗

bioRxiv2023

Cooperativity and induced oligomerisation control the interaction of SARS- CoV-2 with its cellular receptor and patient-derived antibodies

Viral entry is mediated by oligomeric proteins on the virus and cell surfaces. The association is therefore open to multivalent interactions between these proteins, yet such recognition is typically rationalised as affinity between monomeric equivalents. As a result, assessment of the thermodynamic mechanisms that control viral entry has been limited. Here, we use mass photometry to overcome the analytical challenges consequent to multivalency. Examining the interaction between the spike protein of SARS-CoV-2 and the ACE2 receptor, we find that ACE2 induces oligomerisation of spike in a variant-dependent fashion. We also demonstrate that patient-derived antibodies use induced-oligomerisation as a primary inhibition mechanism or to enhance the effects of receptor-site blocking. Our results reveal that naive affinity measurements are poor predictors of potency, and introduce a novel antibody-based inhibition mechanism for oligomeric targets. One-Sentence SummaryMultivalent interactions between viral proteins, cell-surface receptors, and anti-viral antibodies regulate infection and inhibition.

biophysics↗

bioRxiv2023

New structural features of the APC/C revealed by high resolution cryo-EM structures of apo-APC/C and the APC/C CDH1:EMI1 complex

The multi-subunit anaphase-promoting complex/cyclosome (APC/C) is a master regulator of cell division. It controls progression through the cell cycle by timely marking mitotic cyclins and other cell cycle regulatory proteins for degradation. The APC/C itself is regulated by the sequential action of its coactivator subunits CDC20 and CDH1, post-translational modifications, and its inhibitory binding partners EMI1 and the mitotic checkpoint complex (MCC). In this study, we took advantage of the latest developments in cryo-electron microscopy (cryo-EM) to determine the structures of human APC/CCDH1:EMI1 and apo-APC/C at 2.9 [A] and 3.2 [A] resolution, respectively, providing novel insights into the regulation of APC/C activity. The high-resolution maps allowed the unambiguous assignment of a previously unassigned -helix to the N-terminus of CDH1 (CDH11) in the APC/CCDH1:EMI1 ternary complex. We also identified a novel zinc-binding module in APC2 that confers structural stability to APC2, and we confirmed the presence of zinc ions experimentally. Finally, due to the higher resolution and well defined density of these maps, we were able to build, aided by AlphaFold predictions, several intrinsically disordered regions in different APC/C subunits that likely play a role in proper APC/C assembly and regulation of its activity.

cell biology↗

bioRxiv2023

Single cell RNA analysis uncovers the cell differentiation trajectories and functionalization for air breathing of frog lung

The evolution and development of vertebrate lungs have received extensive concerns for the significance in terrestrial adaptation. Amphibians possess the most primitive lungs among tetrapods, underscoring the evolutionary importance of lungs in bridging the transition from aquatic to terrestrial life. However, the intricate process of cell differentiation during amphibian lung development is still lacking. Using single cell RNA-seq, we identified 21 cell types in the developing lung of a land-dwelling frog (Microhyla fissipes). We elucidated that single type of alveolar epithelial cells (AECs) existed in amphibian and the diversity of AECs may correspond to the capacity for terrestrial adaptation in tetrapods. Based on pseudotime trajectories analysis, we revealed previously unrecognized developmental-specific transition cell states of epithelial and endothelial cells supporting the rapid morphogenesis of lung during metamorphic climax. We illustrated the cellular and molecular processes during lung functionalization. These findings uncover the cell differentiation trajectories and functionalization for air breathing of frog lungs and highlight the evolutionary peculiarity of the primitive lungs. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=180 SRC="FIGDIR/small/549571v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@d3188aorg.highwire.dtl.DTLVardef@f049feorg.highwire.dtl.DTLVardef@189f98borg.highwire.dtl.DTLVardef@15e3857_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗