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Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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bioRxiv2020

A High-Performance Genetically Encoded Fluorescent Biosensor for Imaging Physiological Peroxynitrite

Peroxynitrite is a highly reactive nitrogen species (RNS) that plays critical roles in signal transduction, stress response, and numerous human diseases. Advanced molecular tools that permit the selective, sensitive, and non-invasive detection of peroxynitrite is essential for understanding its pathophysiological functions. Here, we present pnGFP-Ultra, a high performance, reaction-based, genetically encodable biosensor for imaging peroxynitrite in live cells. pnGFP-Ultra features a p-boronophenylalanine-modified chromophore as the sensing moiety and exhibits a remarkable 123-fold fluorescence turn-on response towards peroxynitrite while displaying virtually no cross-reaction with other reactive oxygen/nitrogen species, including hydrogen peroxide. To facilitate the expression of pnGFP-Ultra in mammalian cells, we engineered a highly efficient noncanonical amino acid (ncAA) expression system that is broadly applicable to the mammalian expression of proteins containing various ncAAs. pnGFP-Ultra robustly detected peroxynitrite production during interferon {gamma} and lipopolysaccharide-induced immune responses in macrophages, and in amyloid {beta}-activated primary glial cells. Thus, pnGFP-Ultra fills an important technical gap and represents an important new addition to the molecular toolbox in probing RNS biology. In BriefChen et al. report pnGFP-Ultra, a high-performance fluorescent biosensor for minimally invasive and selective imaging of peroxynitrite production in live cells. HighlightsO_LIpnGFP-Ultra is a genetically encoded peroxynitrite biosensor with a 123-fold fluorescence turn-on response C_LIO_LIpnGFP-Ultra exhibits high selectivity toward peroxynitrite, with virtually no crossreaction with hydrogen peroxide C_LIO_LIAn optimized plasmid-based system increases noncanonical amino acid incorporation in mammalian cells by >10 fold C_LIO_LIpnGFP-Ultra robustly detects peroxynitrite production in macrophages and primary glial cells C_LI

biochemistry↗
bioRxiv2020

Effects of scent enrichment on behavioural and physiological indicators of stress in zoo primates - a preliminary study on red-ruffed lemurs and Lar gibbons

Captive breeding is vital for primate conservation, with modern zoos serving a crucial role in breeding populations of threatened species and educating the general public. However, captive populations can experience welfare issues that may also undermine their reproductive success. In order to enhance the well-being of endangered zoo primates, we conducted a study to assess the effects of a new scent enrichment programme on captive red-ruffed lemurs (Varecia rubra), black howler monkeys (Alouatta caraya), siamangs (Symphalangus syndactylus), Lar gibbons (Hylobates lar) and orangutans (Pongo pygmaeus pygmaeus). We combined behavioural observations and faecal endocrinology analyses to evaluate the effects of a series of essential oils (benzoin, lavender, lemongrass) on five captive troops (N = 19) housed at Dudley Zoo & Castle and Twycross Zoo (UK). We recorded observations of natural species-specific and abnormal stress-related behaviours for 480 hr using instantaneous scan sampling. We collected 189 faecal samples and measured the faecal cortisol concentrations using radioimmunoassay. We found a significant effect of the scent enrichment on behaviours, with red-ruffed lemurs and black howler monkeys reducing their social interactions, as well as red-ruffed lemurs and Lar gibbons decreasing their stress-related behaviours, after they were exposed to the series of essential oils. We also found that red-ruffed lemurs displayed a significant increase in faecal glucocorticoids following the exposure to essential oils. Our contradictory findings suggest that the effects of this series of essential oils may change depending on the species-specific social lives and olfactory repertoires of primates. In conclusion, we cannot recommend using these essential oils widely with zoo primates without additional evaluation.

animal behavior and cognition↗
bioRxiv2020

CRISPR screens in physiologic medium reveal conditionally essential genes in human cells

Forward genetic screens across hundreds of diverse cancer cell lines have started to define the genetic dependencies of proliferating human cells and how these vary by genotype and lineage. Most screens, however, have been carried out in culture media that poorly resemble metabolite availability in human blood. To explore how medium composition influences gene essentiality, we performed CRISPR-based screens of human cancer cell lines cultured in traditional versus human plasma-like medium (HPLM). Sets of medium-dependent fitness genes span several cellular processes and can vary with both natural cell-intrinsic diversity and the specific combination of basal and serum components that comprise typical culture media. Notably, we traced the causes for each of three conditional growth phenotypes to the availability of metabolites uniquely defined in HPLM versus traditional media. Our findings reveal the profound impact of medium composition on gene essentiality in human cells, and also suggest general strategies for using genetic screens in HPLM to uncover new cancer vulnerabilities and gene-nutrient interactions.

cancer biology↗
bioRxiv2020

A deeply conserved miR-1 dependent regulon supports muscle cell physiology

Muscles are not only essential for force generation but are also key regulators of systemic energy homeostasis1. Both these roles rely heavily on mitochondria and lysosome function as providers of energy and building blocks, but also as metabolic sensors2-4. Perturbations in these organelles or their crosstalk lead to a wide range of pathologies5. Here, we uncover a deeply conserved regulon of mitochondria and lysosome homeostasis under control of the muscle-specific microRNA miR-1. Animals lacking miR-1 display a diverse range of muscle cell defects that have been attributed to numerous different targets6. Guided by the striking conservation of miR-1 and some of its predicted targets, we identified a set of direct targets that can explain the pleiotropic function of miR-1. miR-1-mediated repression of multiple subunits of the vacuolar ATPase (V-ATPase) complex, a key player in the acidification of internal compartments and a hub for metabolic signaling7,8, and of DCT-1/BNIP3, a mitochondrial protein involved in mitophagy and apoptosis9,10, accounts for the function of this miRNA in C. elegans. Surprisingly, although multiple V-ATPase subunits are upregulated in the absence of miR-1, this causes a loss-of-function of V-ATPase due to altered levels or stoichiometry, which negatively impact complex assembly. Finally, we demonstrate the conservation of the functional relationship between miR-1 and the V-ATPase complex in Drosophila.

cell biology↗
bioRxiv2020

Physiological System Dysregulation in Gene Expression Correlates Negatively with Age

We attempted to identify gene expression systems that dysregulate with age in human peripheral blood samples across five public datasets. Dysregulation of gene ontology (GO)-defined systems was measured using the Mahalanobis distance (DM), a measure of multivariant aberrance. We expected many weak positive DM-age correlations, indicating loss of homeostatic control. Out of the 5180 GO terms tested, we found 230 systems that replicated in at least three datasets. Surprisingly, all 230 systems showed negative DM-age correlations, in contrast to findings with clinical biomarkers. These systems were mostly metabolic functions related to small molecules and nitrogen compounds, transport functions, biosynthetic processes and response to stress functions. These results suggest a loss of responsiveness in these gene expression systems during the aging process, and contrast to some previous literature showing increased gene expression heterogeneity with age.

cell biology↗
bioRxiv2020

TIN2 facilitates TRF1-mediated trans- and cis-interactions on physiologically relevant long telomeric DNA

The shelterin complex consisting of TRF1, TRF2, RAP1, TIN2, TPP1, and POT1, functions to prevent false recognition of telomeres as double-strand DNA breaks, and to regulate telomerase and DNA repair protein access. TIN2 is a core component linking double-stranded telomeric DNA binding proteins (TRF1 and TRF2) and proteins at the 3 overhang (TPP1-POT1). Since knockdown of TIN2 also removes TRF1 and TRF2 from telomeres, determining TIN2s unique mechanistic function has been elusive. Here, we investigated DNA molecular structures promoted by TRF1-TIN2 using complementary single-molecule imaging platforms, including atomic force microscopy (AFM), total internal reflection fluorescence microscopy (TIRFM), and the DNA tightrope assay. We demonstrate that TIN2S and TIN2L isoforms facilitate TRF1-mediated DNA compaction (cis-interactions) and DNA-DNA bridging (trans-interactions) in a telomeric sequence- and length-dependent manner. On the short telomeric DNA substrate (6 TTAGGG repeats), the majority of TRF1 mediated telomeric DNA-DNA bridging events are transient with a lifetime of ~1.95 s. On longer DNA substrates (270 TTAGGG), TIN2 forms multi-protein complexes with TRF1 and stabilizes TRF1-mediated DNA-DNA bridging events that last for at least minutes. Preincubation of TRF1 with its regulator protein Tankyrase 1 significantly reduces TRF1-TIN2 mediated DNA-DNA bridging, whereas TIN2 protects the disassembly of TRF1-TIN2 mediated DNA-DNA bridging upon Tankyrase 1 addition. Our study provides evidence that TIN2 functions to promote TRF1 mediated trans-interactions of telomeric DNA, leading to new mechanistic insight into sister telomere cohesion.

biophysics↗
bioRxiv2020

Effects of relocation on Immunological and physiological measures in squirrel monkeys ( Saimiri boliviensis boliviensis)

In the present study, we have quantified the effects of transport, relocation and acclimate/adapt to their new surroundings on squirrel monkey. These responses are measured in blood samples obtained from squirrel monkeys, at different time points relative to their relocation from their old home to their new home. A variety of immunological assays are performed on the phenotype and function of peripheral blood mononuclear cells (PBMCs) in a group of squirrel monkeys that were transported by road for approximately 10 hours from one facility to another. Using a panel of human antibodies and a set of standardized human immune assays, we evaluated the phenotype of lymphocyte subsets by flow, mitogen-specific immune responses of PBMCs in vitro, and levels of cytokines at various time points including immediately before transport, immediately upon arrival, and after approximately 150 days of acclimation. We observed significant changes in T cells and subsets, NK and B cells (CD4+, CD8+, CD4+/CD8+, CD16+, and CD20+). Mitogen specific (e.g. PHA, PWM and LPS) proliferation responses, IFN-g by ELISPOT assay, and cytokines (IL-2, IL-4 and VEGF) significant changes were observed. Changes seen in the serum chemistry measurements mostly complement those seen in the hematology data. The specific goal was to empirically assess the effects of relocation stress in squirrel monkeys in terms of changes in the numbers and functions of various leukocyte subsets in the blood and the amount of time require for acclimating to their new environment. Such data will help to determine when newly arrived animals become available for use in research studies.

immunology↗
bioRxiv2020

Chlorophyll content and chlorophyll fluorescence as physiological parameters for monitoring Orobanche foetida Poir. infestation on faba bean (Vicia faba L.)

In total, 39 faba bean (Vicia faba L.) advanced lines were evaluated for resistance to broomrape Orobanche foetida under highly infested field conditions. The trials were conducted during two consecutive copping seasons at Oued-Beja Research Station in Tunisia. The advanced lines XAR-VF00.13-1-2-1-2-1 and XBJ90.04-2-3-1-1-1-2A expressed high resistance level to O. foetida exceeding those recorded for resistance checks Najeh and Baraca. Results showed that O. foetida significantly affected the biomass, grain yield, chlorophyll content index (CCI) and the maximum quantum efficiency (Fv/Fm ratio). No significant effect of O. foetida parasitism was observed on host plant water content (WC). O. foetida parasitism significantly affected both CCI and Fv/Fm ratio. CCI decreases varied from 46.4% for the susceptible check Badi and 4.2% and 9.3% observed for the genotypes Baraca and XBJ90.04-2-3-1-1-1-2A. Compared to susceptible check, slight decreases of Fv/Fm ratio were observed for both advanced lines XBJ90.04-2-3-1-1-1-2A and XAR-VF00.13-1-2-1-2-1. Correlation between CCI and Fv/Fm with the resistance to broomrape makes this, easy-to-measure, parameter very useful as a practical screening tool for early parasitism detection, diagnosis and identification and selection of high resistant plants against this pathogen.

genetics↗
bioRxiv2020

A unified physiological framework of transitions between seizures, status epilepticus and depolarization block at the single neuron level

The majority of seizures recorded in humans and experimental animal models can be described by a generic phenomenological mathematical model, The Epileptor. In this model, seizure-like events (SLEs) are driven by a slow variable and occur via saddle node (SN) and homoclinic bifurcations at seizure onset and offset, respectively. Here we investigated SLEs at the single cell level using a biophysically relevant neuron model including a slow/fast system of four equations. The two equations for the slow subsystem describe ion concentration variations and the two equations of the fast subsystem delineate the electrophysiological activities of the neuron. Using extracellular K+ as a slow variable, we report that SLEs with SN/homoclinic bifurcations can readily occur at the single cell level when extracellular K+ reaches a critical value. In patients and experimental models, seizures can also evolve into sustained ictal activity (SIA) and, depolarization block (DB), activities which are also parts of the dynamic repertoire of the Epileptor. Increasing extracellular concentration of K+ in the model to values found during experimental status epilepticus and DB, we show that SIA and DB can also occur at the single cell level. Thus, seizures, SIA and DB, which have been first identified as network events, can exist in a unified framework of a biophysical model at the single neuron level and exhibit similar dynamics as observed in the Epileptor. Author SummaryEpilepsy is a neurological disorder characterized by the occurrence of seizures. Seizures have been characterized in patients in experimental models at both macroscopic and microscopic scales using electrophysiological recordings. Experimental works allowed the establishment of a detailed taxonomy of seizures, which can be described by mathematical models. We can distinguish two main types of models. Phenomenological (generic) models have few parameters and variables and permit detailed dynamical studies often capturing a majority of activities observed in experimental conditions. But they also have abstract parameters, making biological interpretation difficult. Biophysical models, on the other hand, use a large number of variables and parameters due to the complexity of the biological systems they represent. Because of the multiplicity of solutions, it is difficult to extract general dynamical rules. In the present work, we integrate both approaches and reduce a detailed biophysical model to sufficiently low-dimensional equations, and thus maintaining the advantages of a generic model. We propose, at the single cell level, a unified framework of different pathological activities that are seizures, depolarization block, and sustained ictal activity.

neuroscience↗
bioRxiv2020

Physiological and ecological warnings that Dodder pose an exigent threat to farmlands in Eastern Africa

Invasive holoparasitic plants of the genus Cuscuta (dodder) threaten Africas ecosystems, due to their rapid spread and attack on various host plant species. Most Cuscuta species cannot photosynthesize, hence rely on host plants for nourishment. After attachment through a peg-like organ called a haustorium, the parasites deprive hosts of water and nutrients leading to their death. Despite their rapid spread in Africa, dodders have attracted limited research attention, although data on their taxonomy, host range and epidemiology are critical for their management. Here, we combine taxonomy and phylogenetics to reveal presence of field dodder (Cuscuta campestris) and C. kilimanjari (both either naturalized or endemic to East Africa), and for the first time in continental Africa, presence of the giant dodder (C. reflexa) a south Asian species. These parasites have a wide host range, parasitizing species across 13 angiosperm orders. Evaluating the possibility of C. reflexa to expand this host range to tea, coffee, and mango, crops of economic importance to Africa, revealed successful parasitism, following haustorial formation and vascular bundle connections in all three crops. However, only mango mounted a successful post-attachment resistance response. Furthermore, species distribution models predicted high habitat suitability for all three Cuscuta species across major tea- and coffee-growing regions of Eastern Africa, suggesting an imminent risk to these crops. Our findings provide relevant insights into a little-understood threat to biodiversity and economic wellbeing in Eastern Africa, and providing critical information to guide development of management strategies to avert their spread. Sentence SummaryMicroscopy and habitat suitability modeling provide an early warning that dodders invasion in Eastern Africa poses a threat to important cash crops

ecology↗
bioRxiv2020

Root water gates and not changes in root structure provide new insights into plant physiological responses and adaptations to drought, flooding and salinity

The influence of aquaporin (AQP) activity on plant water movement remains unclear, especially in plants subject to unfavorable conditions. We applied a multitiered approach at a range of plant scales to (i) characterize the resistances controlling water transport under drought, flooding and flooding plus salinity conditions; (ii) quantify the respective effects of AQP activity and xylem structure on root (Kroot), stem (Kstem) and leaf (Kleaf) conductances, and (iii) evaluate the impact of AQP-regulated transport capacity on gas exchange. We found that drought, flooding and flooding-salinity reduced Kroot and root AQP activity in Pinus taeda, whereas Kroot of the flood-tolerant Taxodium distichum did not decline under flooding. The extent of the AQP-control of transport efficiency varied among organs and species, ranging from 35%-55% in Kroot to 10%-30% in Kstem and Kleaf. In response to treatments, AQP-mediated inhibition of Kroot rather than changes in xylem acclimation controlled the fluctuations in Kroot. The reduction in stomatal conductance and its sensitivity to vapor pressure deficit were direct responses to decreased whole-plant conductance triggered by lower Kroot and larger resistance belowground. Our results provide new mechanistic and functional insights on plant hydraulics that are essential to quantifying the influences of future stress on ecosystem function.

developmental biology↗
bioRxiv2020

Towards personalized auditory models: predicting individual sensorineural-hearing-loss profiles from recorded human auditory physiology

Over the past decades, different types of auditory models have been developed to study the functioning of normal and impaired auditory processing. Several models can simulate frequency-dependent sensorineural hearing loss (SNHL), and can in this way be used to develop personalized audio-signal processing for hearing aids. However, to determine individualized SNHL profiles, we rely on indirect and non-invasive markers of cochlear and auditory-nerve (AN) damage. Our progressive knowledge of the functional aspects of different SNHL subtypes stresses the importance of incorporating them into the simulated SNHL profile, but has at the same time complicated the task of accomplishing this on the basis of non-invasive markers. In particular, different auditory evoked potential (AEP) types can show a different sensitivity to outer-hair-cell (OHC), inner-hair-cell (IHC) or AN damage, but it is not clear which AEP-derived metric is best suited to develop personalized auditory models. This study investigates how simulated and recorded AEPs can be used to derive individual AN- or OHC-damage patterns and personalize auditory processing models. First, we individualized the cochlear-model parameters using common methods of frequency-specific OHC-damage quantification, after which we simulated AEPs for different degrees of AN-damage. Using a classification technique, we determined the recorded AEP metric that best predicted the simulated individualized CS profiles. We cross-validated our method using the dataset at hand, but also applied the trained classifier to recorded AEPs from a new cohort to illustrate the generalisability of the method.

bioengineering↗
bioRxiv2020

Dynamic integration and segregation of amygdala subregional functional circuits linking to physiological arousal

The dynamical organization of brain networks is essential to support human cognition and emotion for rapid adaption to ever-changing environment. As the core nodes of emotion-related brain circuitry, the basolateral amygdala (BLA) and centromedial amygdala (CMA) as two major amygdalar nuclei, are recognized to play distinct roles in affective functions and internal states, via their unique connections with cortical and subcortical structures in rodents. However, little is known how the dynamical organization of emotion-related brain circuitry reflects internal autonomic responses in humans. Using resting-state functional magnetic resonance imaging (fMRI) with K-means clustering approach in a total of 79 young healthy individuals (cohort 1: 42; cohort 2: 37), we identified two distinct states of BLA- and CMA-based intrinsic connectivity patterns, with one state (integration) showing generally stronger BLA- and CMA-based intrinsic connectivity with multiple brain networks, while the other (segregation) exhibiting weaker yet dissociable connectivity patterns. In an independent cohort 2 of fMRI data with concurrent recording of skin conductance, we replicated two similar dynamic states and further found higher skin conductance level in the integration than segregation state. Moreover, machine learning-based Elastic-net regression analyses revealed that time-varying BLA and CMA intrinsic connectivity with distinct network configurations yield higher predictive values for spontaneous fluctuations of skin conductance level in the integration than segregation state. Our findings highlight dynamic functional organization of emotion-related amygdala nuclei circuits and networks and its links to spontaneous autonomic arousal in humans.

neuroscience↗
bioRxiv2020

Morphological and physiological effects of a single amino acid substitution in the patatin-like phospholipase CapV in Escherichia coli

In rod-shaped bacteria morphological plasticity occurs in response to stress, which blocks cell division to promote filamentation. We demonstrate here that overexpression of the patatin-like phospholipase variant CapVQ329R but not CapV causes pronounced sulA-independent pyridoxine-inhibited cell filamentation and restriction of swimming and flagella production of Escherichia coli K-12 derivative MG1655. Mutational analyses of CapVQ329R indicated conserved amino acids in canonical patatin-like phospholipase A motifs, but not the nucleophilic serine to be required for the observed phenotypes. Furthermore, CapVQ329R alters rdar biofilm formation including expression of the biofilm activator CsgD. Moreover, commensal and pathogenic E. coli strains and Salmonella typhimurium also responded with cell filamentation and alteration in biofilm formation. In conclusion, this work identifies the CapV variant CapVQ329R as a pleiotropic regulator, emphasizes a scaffold function for patatin-like phospholipases and highlights the role of a single amino acid change for the evolution of protein functionality.

microbiology↗
bioRxiv2020

Physiological role of the 3'IgH CBEs super-anchor in antibody class switching

IgH class switch recombination (CSR) replaces C constant region (CH) exons with one of six downstream CHS by joining transcription-targeted DSBs in the C switch (S) region to DSBs in a downstream S region. Chromatin loop extrusion underlies fundamental CSR mechanisms including 3IgH regulatory region (3IgHRR)-mediated S region transcription, CSR center formation, and deletional CSR joining. There are ten consecutive CTCF binding elements (CBEs) downstream of the 3IgHRR, termed the "3IgH CBEs". Prior studies showed that deletion of eight 3IgH CBEs did not detectably affect CSR. Here, we report that deletion of all 3IgH CBEs impacts, to varying degrees, germline transcription and CSR of upstream S regions, except S{gamma}1. Moreover, deletion of all 3IgH CBEs rendered the 6kb region just downstream highly transcribed and caused sequences within to be aligned with S, broken, and joined to form aberrant CSR rearrangements. These findings implicate the 3IgH CBEs as a critical insulator for focusing loop extrusion-mediated 3IgHRR transcriptional and CSR activities on upstream CH locus targets. SignificanceB lymphocytes change antibody heavy chain (IgH) isotypes by a recombination/deletion process called IgH class switch recombination (CSR). CSR involves introduction of DNA breaks into a donor switch (S) region and also into one of six downstream S regions, with joining of the breaks changing antibody isotype. A chromatin super-anchor, of unknown function, is located just downstream of the IgH locus. We show that complete deletion of this super-anchor variably decreases CSR to most S regions and creates an ectopic S region downstream of IgH locus that undergoes aberrant CSR-driven chromosomal rearrangements. Based on these and other findings, we conclude that the super-anchor downstream of IgH is a critical insulator for focusing potentially dangerous CSR rearrangements to the IgH locus.

immunology↗
bioRxiv2020

CAZymes in Maribacter dokdonensis 62-1 from the Patagonian shelf: Genomics and physiology compared to related flavobacteria and a co-occurring Alteromonas strain

Carbohydrate-active enzymes (CAZymes) are an important feature of bacteria in productive marine systems such as continental shelves, where phytoplankton and macroalgae produce diverse polysaccharides. We herein describe Maribacter dokdonensis 62-1, a novel strain of this flavobacterial species, isolated from alginate-supplemented seawater collected at the Patagonian continental shelf. M. dokdonensis 62-1 harbors a diverse array of CAZymes in multiple polysaccharide utilization loci (PUL). Two PUL encoding polysaccharide lyases from families 6, 7, 12 and 17 allow substantial growth with alginate as sole carbon source, with simultaneous utilization of mannuronate and guluronate as demonstrated by HPLC. Furthermore, strain 62-1 harbors a mixed-feature PUL encoding both ulvan- and fucoidan-targeting CAZymes. Core-genome phylogeny and pangenome analysis revealed variable occurrence of these PUL in related Maribacter and Zobellia strains, indicating specialization to certain "polysaccharide niches". Furthermore, lineage- and strain-specific genomic signatures for exopolysaccharide synthesis possibly mediate distinct strategies for surface attachment and host interaction. The wide detection of CAZyme homologs in algae-derived metagenomes suggests global occurrence in algal holobionts, supported by sharing multiple adaptive features with the hydrolytic model flavobacterium Zobellia galactanivorans. Comparison with Alteromonas sp. 76-1 isolated from the same seawater sample revealed that these co-occurring strains target similar polysaccharides but with different genomic repertoires, coincident with differing growth behavior on alginate that might mediate ecological specialization. Altogether, our study contributes to the perception of Maribacter as versatile flavobacterial polysaccharide degrader, with implications for biogeochemical cycles, niche specialization and bacteria-algae interactions in the oceans.

microbiology↗
bioRxiv2020

Cell-type specific analysis of physiological action of estrogen in mouse oviducts

One of the endogenous estrogens, 17{beta}-estradiol (E2) is a female steroid hormone secreted from the ovary. It is well established that E2 causes biochemical and histological changes in the uterus. The oviduct response to E2 is virtually unknown in an in vivo environment. In this study, we assessed the effect of E2 on each oviductal cell type, using an ovariectomized-hormone-replacement mouse model, single cell RNA-sequencing (scRNA-seq), in situ hybridization, and cell-type-specific deletion in mice. We found that each cell type in the oviduct responded to E2 distinctively, especially ciliated and secretory epithelial cells. The treatment of exogenous E2 did not drastically alter the transcriptomic profile from that of endogenous E2 produced during estrus. Moreover, we have identified and validated genes of interest in our datasets that may be used as cell- and region-specific markers in the oviduct. Insulin-like growth factor 1 (Igf1) was characterized as an E2-target gene in the mouse oviduct and was also expressed in human Fallopian tubes. Deletion of Igf1 in progesterone receptor (Pgr)-expressing cells resulted in female subfertility, partially due to an embryo developmental defect and embryo retention within the oviduct. In summary, we have shown that oviductal cell types are differentially regulated by E2 and support gene expression changes that are required for normal embryo development and transport in mouse models.

cell biology↗