Biology subjects

Trimm, E.

Publications and source records attributed to Trimm, E..

5 recordsLinked to original sources

bioRxiv2026

A Perturb-seq screen guided by species divergence uncovers pathways for collateral artery formation

Collateral arteries are natural bypasses that can reroute blood flow around arterial blockages, limiting tissue injury during stroke and coronary artery disease. Despite their clinical effectiveness, therapeutic strategies to stimulate collateral artery growth remain unavailable due to our limited understanding of their developmental mechanisms. Remarkably, guinea pigs display exceptionally dense collateral artery networks across various organs, resulting in complete resistance to ischemic damage in the brain and heart. In this study, we compared single-cell RNA sequencing (scRNA-seq) from guinea pig and mouse tissues to identify endothelial cell (EC) gene expression patterns associated with extensive collateral artery development. We then developed an in vivo Perturb-seq platform in mice to test whether genes differentially expressed in guinea pigs influence artery EC specification. This pipeline identified artery repressors that were downregulated in guinea pigs and increased pial collateral abundance when inhibited in mice. Downstream analysis suggests that artery repressors, including WNT and hypoxia response genes, function in two capillary EC subsets--Esm1+ pre-artery and Apln+ angiogenic tip cells. Reduced activity of these repressors allows more ECs to acquire arterial identity, potentiating collateral artery formation. Collectively, our study establishes a strategy for discovering the genes underlying species-specific traits, suggests that guinea pigs have collaterals due to decreased activity of artery inhibitor pathways and hypoxia responses, and identifies novel targets for stimulating collateral artery formation (Graphical abstract). O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=174 SRC="FIGDIR/small/721711v2_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@18b36cdorg.highwire.dtl.DTLVardef@bafbaforg.highwire.dtl.DTLVardef@1e1a6bdorg.highwire.dtl.DTLVardef@189f585_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2025

VEGF/ERK activation and PI3K inhibition together drive a vein-to-artery transition in an in vitro model of human angiogenesis

Artery endothelial cells (ECs) arise through different pathways, including differentiation from mesodermal cells (vasculogenesis) or from already established vein or capillary plexus ECs (angiogenesis), the latter being most common during embryonic development and regeneration. Understanding the vein-to-artery (v2a) transition could improve revascularization therapies, but progress is limited by a lack of human models. Here, we develop a human pluripotent stem cell (hPSC) differentiation protocol that models the v2a EC conversion. Comparing v2a and mesoderm-to-artery (m2a) transcriptomes with publicly available single cell RNA sequencing (scRNA-seq) data from human embryos showed they reflected angiogenesis- and vasculogenesis-derived artery ECs, respectively. This reductionist system revealed that VEGF activation alongside PI3K inhibition was sufficient for vein ECs to acquire arterial identity within 48 hours. We model a critical step in vascular development and define the minimal signals required for artery differentiation from veins, providing a framework to promote this conversion in revascularization or therapeutic contexts.

developmental biology↗

bioRxiv2024

An egg sabotaging mechanism drives non-Mendelian transmission in mice

During meiosis, homologous chromosomes segregate so that alleles are transmitted equally to haploid gametes, following Mendels Law of Segregation. However, some selfish genetic elements drive in meiosis to distort the transmission ratio and increase their representation in gametes. The established paradigms for drive are fundamentally different for female vs male meiosis. In male meiosis, selfish elements typically kill gametes that do not contain them. In female meiosis, killing is predetermined, and selfish elements bias their segregation to the single surviving gamete (i.e., the egg in animal meiosis). Here we show that a selfish element on mouse chromosome 2, R2d2, drives using a hybrid mechanism in female meiosis, incorporating elements of both male and female drivers. If R2d2 is destined for the polar body, it manipulates segregation to sabotage the egg by causing aneuploidy that is subsequently lethal in the embryo, so that surviving progeny preferentially contain R2d2. In heterozygous females, R2d2 orients randomly on the metaphase spindle but lags during anaphase and preferentially remains in the egg, regardless of its initial orientation. Thus, the egg genotype is either euploid with R2d2 or aneuploid with both homologs of chromosome 2, with only the former generating viable embryos. Consistent with this model, R2d2 heterozygous females produce eggs with increased aneuploidy for chromosome 2, increased embryonic lethality, and increased transmission of R2d2. In contrast to a male meiotic driver, which kills its sister gametes produced as daughter cells in the same meiosis, R2d2 eliminates "cousins" produced from meioses in which it should have been excluded from the egg.

genetics↗

bioRxiv2018

Molecular and evolutionary strategies of meiotic cheating by selfish centromeres

Asymmetric division in female meiosis creates selective pressure favoring selfish centromeres that bias their transmission to the egg. This centromere drive can explain the paradoxical rapid evolution of both centromere DNA and centromere-binding proteins despite conserved centromere function. Here, we define a molecular pathway linking expanded centromeres to histone phosphorylation and recruient of microtubule destabilizing factors in an intraspecific hybrid, leading to detachment of selfish centromeres from spindle microtubules that would direct them to the polar body. We also introduce a second hybrid model, exploiting centromere divergence between species, and show that winning centromeres in one hybrid become losers in the other. Our results indicate that increasing destabilizing activity is a general strategy for drive, but centromeres have evolved distinct strategies to increase that activity. Furthermore, we show that drive depends on slowing meiotic progression, suggesting that a weakened meiotic spindle checkpoint evolved as a mechanism to suppress selfish centromeres.

cell biology↗

bioRxiv2017

Spindle asymmetry drives non-Mendelian chromosome segregation

Genetic elements compete for transmission through meiosis, when haploid gametes are created from a diploid parent. Selfish elements can enhance their transmission through meiotic drive, in violation of Mendels Law of Segregation. In female meiosis, selfish elements drive by preferentially attaching to the egg side of the spindle, which implies some asymmetry between the two sides of the spindle, but molecular mechanisms underlying spindle asymmetry are unknown. Here we show that CDC42 signaling from the cell cortex regulates microtubule tyrosination to induce spindle asymmetry, and non-Mendelian segregation depends on this asymmetry. These signals depend on cortical polarization directed by chromosomes, which are positioned near the cortex to allow the asymmetric cell division. Thus, selfish meiotic drivers exploit the asymmetry inherent in female meiosis to bias their transmission.

cell biology↗