Biology subjects

Dewar, A.

Publications and source records attributed to Dewar, A..

7 recordsLinked to original sources

bioRxiv2026

ERBB2 establishes the timing of progesterone priming required for uterine receptivity

Progesterone is essential for establishing uterine receptivity and sustaining early pregnancy. However, how the uterus acquires the competence to respond to progesterone at the appropriate time remains poorly understood. Here we show that ERBB2 governs the timing of progesterone responsiveness required for uterine receptivity. In endometrial samples from women with recurrent spontaneous abortion (RSA), ERBB2 is downregulated specifically in the stromal compartment, accompanied by a parallel reduction in stromal progesterone receptor (PGR). Uterine deletion of Erbb2 in mice blunts the rise of stromal PGR at the onset of the receptive window, deferring implantation and impairing decidualization despite normal circulating progesterone and estrogen. Epithelial deletion has no such effect, placing the requirement in the stroma. High-dose progesterone fails to rescue the phenotype; advancing progesterone priming by 24 hours restores stromal PGR, HAND2, Bmp2, and on-time implantation. Collectively, the present study provides evidence that ERBB2 directs the temporal window of stromal progesterone priming by setting the threshold for PGR induction, thereby synchronizing the maternal-fetal interface and safeguarding pregnancy.

developmental biology↗

bioRxiv2025

Uterine stromal Erbb3-Igf1 signaling is critical to functional gland development conducive to implantation

Preimplantation uterine gland differentiation, involving glandular branching, is a prerequisite for secretion of leukemia inhibitory factor (LIF), thereby establishing uterine receptivity to embryo implantation. This differentiation process is disrupted by the absence of FOXA2, a transcription factor specifically present in uterine glands. It remains unclear whether preimplantation glandular differentiation is regulated exclusively by gland-intrinsic mechanisms or is influenced by the surrounding microenvironment through mesenchymal-epithelial interactions. We show here that uterine deletion of Erbb3 leads to impaired gland branching and FOXA2 expression, as well as reduced female fertility. In contrast, females with uterine epithelial-specific deletion of Erbb3 show normal fertility, suggesting a critical role of stromal ERBB3 signaling. A transcriptomic profiling of day 3 stromal cells identified Igf1 as a candidate paracrine factor mediating the stromal-epithelial interaction. Thus, the uterine deletion of Igf1r leads to a reduced gland branching phenotype similar to that observed in Erbb3d/d uteri. These results demonstrate that ERBB3 regulates glandular branching and embryo implantation via the ERBB3-IGF1-IGF1R signaling pathway.

developmental biology↗

bioRxiv2025

Microbiome-Dependent Functional Responses to Structurally Distinct Oligosaccharides Revealed by Metaproteomics

Dietary oligosaccharides are prebiotics that fuel gut microbes, but individual microbiomes may respond differently depending on oligosaccharide structures as well as microbiome composition and function. The extent to which specific gut microbial communities exhibit personalized functional responses to distinct oligosaccharides remains underexplored. We applied a standardized ex vivo microbiome culture, called RapidAIM, coupled with metaproteomics to examine how six structurally diverse oligosaccharides affect the gut microbiota functional response. Our study shows that while human gut microbiomes share some commonalities in utilizing oligosaccharides (e.g. prioritizing dietary fibers over mucin), the fine-scale metabolic and taxonomic responses are highly individualized. Such findings underscore the importance of considering personal microbiome profiles when predicting the outcome of prebiotic interventions. In a broader context, our metaproteomic approach provides a framework for identifying optimal prebiotic choices tailored to individual microbiomes. Ultimately, understanding these personalized responses could inform precision nutrition strategies.

microbiology↗

bioRxiv2023

SOCfinder: a genomic tool for identifying cooperative genes in bacteria

Bacteria cooperate by working collaboratively to defend their colonies, share nutrients, and resist antibiotics. Nevertheless, our understanding of these remarkable behaviours primarily comes from studying a few well-characterized species. Consequently, there is a significant gap in our understanding of microbial cooperation, particularly in natural environments. To address this gap, we can use bioinformatic tools to identify cooperative traits and their underlying genes across diverse species. Existing tools address this challenge through two approaches. One approach is to identify genes that encode extracellular proteins, which can provide benefits to neighbouring cells. An alternative approach is to predict gene function using annotation tools. However, these tools have several limitations. Not all extracellular proteins are cooperative, and not all cooperative behaviours are controlled by extracellular proteins. Furthermore, existing functional annotation methods frequently miss known cooperative genes. Here, we introduce SOCfinder as a new tool to find cooperative genes in bacterial genomes. SOCfinder combines information from several methods, considering if a gene is likely to (1) code for an extracellular protein, (2) have a cooperative functional annotation, or (3) be part of the biosynthesis of a cooperative secondary metabolite. We use data on two extensively-studied species (P. aeruginosa & B. subtilis) to show that SOCfinder is better at finding known cooperative genes than existing tools. We also use theory from population genetics to identify a signature of kin selection in SOCfinder cooperative genes, which is lacking in genes identified by existing tools. SOCfinder opens up a number of exciting directions for future research, and is available to download from https://github.com/lauriebelch/SOCfinder. Data SummaryAll code and associated files are available at https://github.com/lauriebelch/SOCfinder. Impact StatementBacteria cooperate by secreting many molecules outside the cell, where they can provide benefits to other cells. While we know much about how bacteria cooperate in the lab, we know much less about bacterial cooperation in nature. Is cooperation equally important in all species? Are all cooperations equally vulnerable to cheating? To answer these questions, we need a way of identifying cooperative genes across a wide range of genomes. Here, we provide such a method - which we name SOCfinder. SOCfinder allows users to find cooperative genes in any bacterial genome. SOCfinder opens up a number of exciting directions for future research. It will allow detailed studies of non-model species, as well as broad comparative studies across species. These studies will allow cooperation in the wild to be studied in new ways.

evolutionary biology↗

bioRxiv2023

Familiarity-taxis: A bilateral approach to view-based navigation.

Many insects use view-based navigation, or snapshot matching, to return to familiar locations, or navigate routes. This relies on egocentric memories being matched to current views of the world. Previous snapshot navigation algorithms have used full panoramic vision for the comparison of memorised images with query images to establish a measure of familiarity, which leads to a recovery of the original heading direction from when the snapshot was taken. Many aspects of insect sensory systems are lateralised with steering being derived from the comparison of left and right signals like a classic Braitenberg vehicle. Here we investigate whether view-based route navigation can be implemented using bilateral visual familiarity comparisons. We found that the difference in familiarity between estimates from left and right fields of view can be used as a steering signal to recover the original heading direction. This finding extends across many different sizes of field of view and visual resolutions. In insects, steering computations are implemented in a brain region called the Lateral Accessory Lobe, within the Central Complex. In a simple simulation we show with a SNN model of the LAL an existence proof of how bilateral visual familiarity could drive a search for a visually defined goal.

animal behavior and cognition↗

bioRxiv2022

Targeted deletion of uterine glandular Foxa2 induces embryonic diapause in mice

Embryonic diapause is a reproductive strategy in which embryo development and growth is temporarily arrested within the uterus to ensure the survival of neonates and mothers during unfavorable conditions. Pregnancy is reinitiated when conditions become favorable for neonatal survival. The mechanism of how the uterus enters diapause remains unclear. Mice with uterine deletion of Foxa2, a transcription factor, are infertile. In this study, we show that dormant blastocysts are recovered from these mice on day 8 of pregnancy with persistent uterine Msx1 expression, a gene critical to maintaining the uterine quiescent state, suggesting that these mice enter embryonic diapause. Leukemia inhibitory factor (LIF) can resume implantation in these mice. Although estrogen is critical for implantation in progesterone (P4)-primed uterus, our current model reveals that FOXA2-independent estrogenic effects are detrimental to sustaining uterine quiescence. Interestingly, P4 and anti-estrogen can prolong uterine quiescence in the absence of FOXA2. While we find that Msx1 expression persists in the uterus deficient in Foxa2, the complex relationship of FOXA2 with Msx genes and estrogen receptors remains to be explored.

developmental biology↗

bioRxiv2020

Pregnancy success in mice requires appropriate cannabinoid receptor signaling for primary decidua formation

An early event after implantation is stromal cell transformation to decidual cells (decidualization) that support embryo development. In mice, this process begins at the antimesometrial (AM) pole with differentiation of stromal cells into epithelial-like cells (epithelioid cells) surrounding the implantation chamber. This is an avascular zone called the primary decidual zone (PDZ), and considered to function as a transient, size-dependent permeable barrier to protect the embryo from maternal circulating harmful agents, including immunoglobulins, immune cells, microorganisms and other noxious agents. This zone forms on day 5 afternoon and becomes fully established on day 6 with the loss of the crypt epithelium. The PDZ gradually degenerates with the appearance of the secondary decidual zone (SDZ) around the PDZ that peaks on day 8 in mice. Decidualization is critical for early pregnancy in mice and humans. We show that cannabinoid/endocannabinoid signaling influences decidualization in early pregnancy. Mice deficient in two major cannabinoid receptors, CB1 and CB2, show compromised PDZ. We found that angiogenic factors are dysregulated in Cnr1-/-Cnr2-/- mice with defective PDZs, resulting in the abnormal presence of blood vessels and macrophages in this zone; disruption of the PDZ compromises pregnancy outcomes. Using an in vitro decidualization model, we found that Cnr1 levels increase in mouse stromal cells and human uterine fibroblast (Huf) cells undergoing decidualization and that limiting CB1 signaling in these cell types suppresses decidualization in vitro. Since endothelial cells express Cnr2 and decidual cells express Cnr1, we hypothesize that angiogenic events driven by CB2 are integrated with CB1 in decidual cells, leading to proper PDZ formation, a critical step for pregnancy success.

developmental biology↗