Biology subjects

Pavlicev, M.

Publications and source records attributed to Pavlicev, M..

7 recordsLinked to original sources

bioRxiv2025

Precocial ancestry of placental mammals

1Mammals exhibit two distinct reproductive strategies: altriciality, where neonates are highly underdeveloped, and precociality, where neonates are well-developed. The neonatal developmental state of deep nodes in mammalian phylogeny remains unresolved. Here, we use phylogenetic comparative methods to reconstruct the evolutionary history of neonatal maturity in mammals and demonstrate that the eutherian ancestor likely gave birth to precocial neonates. This finding contradicts the prevailing view that precociality evolved multiple times within the eutherian lineage. We contextualize this result with three lines of evidence. First, recent fossil evidence suggests that precocial life history traits arose early in therian evolution. Second, altricial eutherian neonates are markedly more developed at birth compared to altricial non-eutherians, suggesting a precocial ancestry in eutherian evolution. Third, reproductive traits that enable prolonged pregnancy originated in the stem lineage prior to the eutherian ancestor. Based on these findings, we propose an alternative model for the evolutionary history of precociality in mammals.

evolutionary biology↗

bioRxiv2024

Hallmarks of uterine receptivity predate placental mammals

Embryo implantation is essential to pregnancy in eutherian (placental) mammals. The cellular changes that enabled invasive implantation to evolve from superficial embryo apposition, the ancestral condition still retained in marsupials, have remained unclear. We generated and compared single-cell transcriptomes from the peri-implantation and non-pregnant uterus of two rodents with invasive implantation, the mouse and the guinea pig, and the opossum, a marsupial lacking invasive implantation. Cross-species analysis of endometrial cell types and ligand-receptor signaling revealed that the opossum blastocyst-stage uterus, despite lacking fetal-maternal contact, shares key features with the eutherian window of receptivity. These include a window in which the epithelial-stromal IHH-PTCH1 axis is active, but the downstream BMP2-mediated signaling that enables decidualization in eutherians is antagonized through a temporary spike in glandular GREM2. We propose that a homologous progesterone-responsive endometrial remodeling reaction preceded the evolution of eutherian and marsupial modes of implantation in their respective lineages. Complementary analysis of pre- and post-implantation embryonic transcriptomes from the same species revealed broad conservation of implantation-related functional genes in the blastocyst, as well as a remarkable similarity in ligand production between the mature trophoblast and the luminal epithelium. We suggest that this redundancy between trophectoderm and luminal epithelial signaling was an enabling factor for the evolution of invasive placentation. Together, these findings suggest that eutherian implantation evolved by maternal rewiring of the output of an ancestral window of receptivity-like epithelial-stromal signaling axis toward decidualization, stabilized epithelial loss, and invasion. Significance StatementPregnancy in placental mammals begins with implantation and invasion of the embryo, whereas marsupials retain a superficial mode of embryo apposition. How this major evolutionary transition occurred is unknown. Comparing uterine and embryonic single-cell transcriptomes between model rodents and the opossum reveals that the marsupial uterus activates an epithelial-stromal signaling axis canonically associated with receptivity to implantation. In the marsupial uterus, its outputs are opposed by inhibitory signals, whereas in placental mammals, this program promotes uterine decidual transformation and invasion. Early-embryo implantation-related gene expression, in contrast, shows little change across species. These results challenge the view that implantation evolved through the gain of invasive properties by the embryo, and reveal a common developmental foundation from which placentals evolved their novel mode of gestation.

evolutionary biology↗

bioRxiv2024

Comparative single cell analysis reveals complex patterns of cell type and cell signaling innovations at the fetal-maternal interface

How fetal and maternal cell types have co-evolved to enable mammalian placentation poses a unique evolutionary puzzle. Here, we present a multi-species atlas integrating single-cell transcriptomes from six species bracketing therian mammal diversity. We find that invasive trophoblasts share a gene-expression signature across eutherians, and evidence that endocrine decidual cells evolved stepwise from an immunomodulatory cell type retained in Tenrec with affinity to human decidua of menstruation. We recover evolutionary patterns in ligand-receptor signaling: fetal and maternal cells show a pronounced tendency towards disambiguation, but a predicted arms race dynamic between them is limited. We reconstruct cell communication networks of extinct mammalian ancestors, finding strong integration of fetal trophoblast into maternal networks. Together, our results reveal a dynamic history of cell type and signaling evolution. SynopsisThe fetal-maternal interface is one of the most intense loci of cell-cell signaling in the human body. Invasion of cells from the fetal placenta into the uterus, and the corresponding transformation of maternal tissues called decidualization, first evolved in the stem lineage of eutherian mammals(1, 2). Single-cell studies of the human fetal-maternal interface have provided new insight into the cell type diversity and cell-cell interactions governing this chimeric organ(3-5). However, the fetal-maternal interface is also one of the most rapidly evolving, and hence most diverse, characters among mammals(6), and an evolutionary analysis is missing. Here, we present and compare single-cell data from the fetal-maternal interface of species bracketing key events in mammal phylogeny: a marsupial (opossum, Monodelphis domestica), the afrotherian Tenrec ecaudatus, and four Euarchontoglires - guinea pig and mouse (Rodentia) together with recent macaque and human data (primates) (4, 5, 7). We infer cell type homologies, identify a gene-expression signature of eutherian invasive trophoblast conserved over 99 million years, and discover a predecidual cell in the tenrec which suggests stepwise evolution of the decidual stromal cell. We reconstruct ancestral cell signaling networks, revealing the integration of fetal cell types into the interface. Finally, we test two long-standing theoretical predictions, the disambiguation hypothesis(8) and escalation hypothesis(9), at transcriptome-wide scale, finding divergence between fetal and maternal signaling repertoires but arms race dynamics restricted to a small subset of ligand-receptor pairs. In so doing, we trace the co-evolutionary history of cell types and their signaling across mammalian viviparity.

evolutionary biology↗

bioRxiv2022

A SNP affects Wnt4 expression in endometrial stroma, with antagonistic implications for pregnancy, endometriosis and reproductive cancers

The common human single nucleotide polymorphism rs3820282 is associated with multiple phenotypes ranging from gestational length to likelihood of endometriosis and ovarian cancer and can thus serve as a paradigm for a highly pleiotropic genetic variant. Pleiotropy makes it challenging to assign specific causal roles to particular genetic variants. Deleterious mutations in multifunctional genes may cause either the co-occurrence of multiple disorders in the same individuals (i.e., syndromes), or be repeatedly associated with a variety of disorders in a population. Moreover, the adverse effects can occur in combination with advantages in other traits, maintaining high frequencies of deleterious alleles in the population. To reveal the causal role of this specific SNP, we investigated the molecular mechanisms affected by rs3820282 in mice. We have shown previously that rs3820282 introduces a high affinity estrogen receptor 1 binding site at the Wnt4 locus. Having introduced this nucleotide substitution into the homologous site of the mouse genome by CRISPR/Cas 9 we show that this change causes a specific upregulation of Wnt4 transcription in the endometrial stromal cells during the preovulatory estrogen peak in late proestrus. Transcriptomic analysis of the whole uterus reveals broad systemic effects on uterine gene expression, including downregulation of proliferation and induction of many progesterone-regulated pro-implantation genes. The effect on proliferation is limited to the luminal epithelium, whereas other effects involve the uterine stromal compartment. We suggest that in the uterus, these changes could contribute to increased permissiveness to embryo invasion. Yet in other estrogen-responsive tissues, the same changes potentially lead to decreased resistance to invasion by cancer cells and endometriotic foci. A single molecular effect of rs3820282 on Wnt4 expression may thus underlie the various associated phenotypic effects.

genetics↗

bioRxiv2020

Endogenous retroviruses drive species-specific germline transcriptomes in mammals

Gene regulation in the germline ensures the production of high-quality gametes, long-term maintenance of the species, and speciation. Germline transcriptomes undergo dynamic changes after the mitosis-to-meiosis transition in males and have been subject to evolutionary divergence among mammals. However, the mechanism that underlies germline regulatory divergence remains undetermined. Here, we show that endogenous retroviruses influence species-specific germline transcriptomes in mammals. We show that the expression of endogenous retroviruses, particularly the evolutionarily young K family (ERVK), is associated with gene activation after the mitosis-to-meiosis transition in male mice. We demonstrate that accessible chromatin and H3K27ac, a marker of active enhancers, are tightly associated with ERVK loci as well as with the activation of neighboring evolutionarily young germline genes. Thus, ERVKs serve as evolutionarily novel enhancers in mouse spermatogenesis. These ERVK loci bear binding motifs for critical regulators of spermatogenesis such as A-MYB. The genome-wide transposition of ERVKs might have rewired germline gene expression in a species-specific manner. Notably, these features are present in human spermatogenesis, but independently evolved ERVs are associated with expression of germline genes, demonstrating the prevalence of ERV-driven mechanisms in mammals. Together, we propose a model whereby species-specific transcriptomes are fine-tuned by endogenous retroviruses in the mammalian germline.

developmental biology↗

bioRxiv2019

The Evolution of Placental Invasion and Cancer Metastasis are Causally Linked

Among mammals, the extent of placental invasion is correlated with vulnerability to malignancy. Animals with more invasive placentation (e.g. humans) are more vulnerable to malignancy, whereas animals with a non-invasive placenta (e.g. ruminants) are less likely to develop malignant cancer. To explain this correlation, we propose the hypothesis of Evolved Levels of Invasibility (ELI) positing that the permissiveness of stromal tissue to invasion is a unitary character affecting both placental and cancer invasion. We provide evidence for this hypothesis by contrasting invasion of human and bovine cancer and placental cells into a lawn of stromal cells from different species. We find that both bovine endometrial and skin fibroblasts are more resistant to invasion of placental and cancer cells than their human counterparts. Gene expression profiling identified genes with high expression in human but not bovine fibroblasts. Knocking down of a subset of them in human fibroblasts leads to significantly stronger resistance to cancer cell invasion. Comparative analysis of gene expression among mammals suggests that humans evolved higher vulnerability to malignancy than the eutherian ancestor, possibly as a correlate of more invasive placentation, and boroeutherians evolved to decrease stromal invasibility. Identifying the evolutionary determinants of stromal invasibility can provide significant insights to develop rational anti-metastatic therapeutics.

cancer biology↗

bioRxiv2018

Evolution of embryo implantation was enabled by the origin of decidual cells in eutherian mammals

Embryo implantation is the first step in the establishment of pregnancy in eutherian (Placental) mammals. Although viviparity evolved prior to the common ancestor of marsupials and eutherian mammals (therian ancestor), implantation is unique to eutherians. The ancestral therian pregnancy likely involved a short phase of attachment between the fetal and maternal tissues followed by parturition rather than implantation, similar to the mode of pregnancy found in marsupials such as the opossum. Embryo implantation in eutherian mammals as well as embryo attachment in opossum, induce a homologous inflammatory response in the uterus. Here, we elucidate the evolutionary mechanism by which the ancestral inflammatory fetal-maternal attachment was transformed into the process of implantation. We performed a comparative transcriptomic and immunohistochemical study of the gravid and non-gravid uteri of two eutherian mammals, armadillo (Dasypus novemcinctus) and hyrax (Procavia capensis); a marsupial outgroup, opossum (Monodelphis domestica); and compared it to previously published data on rabbit (Oryctolagus cuniculus). This taxon sampling allows inference of the eutherian ancestral state. Our results show that in the eutherian lineage, the ancestral inflammatory response was domesticated by suppressing a detrimental component viz. signaling by the cytokine IL17A, while retaining components that are beneficial to placentation, viz. angiogenesis, vascular permeability, remodeling of extracellular matrix. IL17A mediates recruitment of neutrophils to inflamed mucosal tissues, which, if unchecked, can damage the uterus as well as the embryo and lead to expulsion of the fetus. We hypothesized that the uterine decidual stromal cells, which evolved coincidentally with embryo implantation, evolved, in part, to prevent IL17A-mediated neutrophil infiltration. We tested a prediction of this hypothesis in vitro, and showed that decidual stromal cells can suppress differentiation of human naive T cells into IL17A-producing Th17 cells. Together, these results provide a mechanistic understanding of early stages of the evolution of the eutherian mode of pregnancy, and also identify a potentially ancestral function of an evolutionary novelty, the decidual stromal cell-type.

evolutionary biology↗