Biology subjects

Rattner, A.

Publications and source records attributed to Rattner, A..

4 recordsLinked to original sources

bioRxiv2026

Wnt/beta-catenin signaling regulates Vascular Endothelial Growth Factor (VEGF) receptors in central nervous system endothelial cells

In CNS endothelial cells (ECs), VEGF signaling promotes vascular permeability, and Wnt/beta-catenin signaling reduces vascular permeability by controlling the gene expression program for the blood-brain barrier. Here we show, using genetic mosaics, that, in mouse brain ECs in vivo, an increase in Wnt/beta-catenin signaling produces an increase in VEGFR1 levels and a decrease in VEGFR2 levels, and a decrease in Wnt/beta-catenin signaling produces a decrease in VEGFR1 levels and an increase in VEGFR2 levels. As VEGFR1 functions as a decoy receptor to reduce VEGF signaling through VEGFR2, these data imply that Wnt/beta-catenin signaling acts at the receptor level to reduce VEGF signaling. In HEK/293T cells, VEGF signaling is suppressed by Wnt/beta-catenin signaling in a dose-dependent manner, with nearly complete suppression observed at levels of Wnt/beta-catenin signaling that produce little or no change in VEGF receptor levels. These data reveal two mechanisms by which VEGF signaling is regulated by Wnt/beta-catenin signaling.

developmental biology↗

bioRxiv2026

Endothelial TLR4 signaling drives tissue inflammation, Claudin-5 internalization, and vascular barrier breakdown in a mouse model of neonatal meningitis

Neonatal bacterial meningitis is a leading cause of infant morbidity and mortality, yet the molecular and cellular basis of the leptomeningeal response to infection remains poorly defined. Here, we study a mouse model of neonatal E. coli meningitis, combining conditional gene knockouts, leptomeningeal single-nucleus RNA sequencing, and endothelial cell culture to explore the role of Toll-like receptor 4 (TLR4) signaling in the host response to infection. Deletion of Tlr4 in non-myeloid cells dramatically reduced the inflammatory response in all leptomeningeal cell types and abrogated the infection- associated increase in vascular permeability. In a brain endothelial cell line (bEnd.3 cells), exposure to E. coli triggered NF-{kappa}B activation, selective internalization of Claudin- 5, and increased monolayer permeability, responses that were eliminated by Tlr4 knockout. RNA-seq showed that TLR4 controls an NF-{kappa}B-driven transcriptional program that orchestrates the endothelial response to E. coli. These findings reveal multiple TLR4-dependent host responses to neonatal Gram-negative bacterial meningitis.

pathology↗

bioRxiv2025

Vascular endothelial-specific loss of TGF-beta signaling as a model for choroidal neovascularization and central nervous system vascular inflammation

In mice, postnatal endothelial cell (EC)-specific knockout of the genes coding for Transforming Growth Factor-Beta Receptor (TGFBR)1 and/or TGFBR2 eliminates TGF-beta signaling in vascular ECs and leads to distinctive central nervous system (CNS) vascular phenotypes. Knockout mice exhibit (1) reduced intra-retinal vascularization, (2) choroidal neovascularization with occasional anastomoses connecting choroidal and intraretinal vasculatures, (3) infiltration of diverse immune cells into the retina, including macrophages, T-cells, B-cells, NK cells, and dendritic cells, (4) a close physical association between immune cells and retinal vasculature, (5) a pro-inflammatory transcriptional state in CNS ECs, with increased ICAM1 immunoreactivity, and (6) increased Smooth Muscle Actin immunostaining in CNS pericytes. Comparisons of the retinal phenotype with two other genetic models of retinal hypovascularization - loss of Norrin/Fzd4 signaling and loss of VEGF signaling - shows that the immune cell infiltrate is greatest with loss of TGF-beta signaling, more modest with loss of Norrin/Fzd4 signaling, and undetectable with loss of VEGF signaling. The phenotypes caused by loss of TGF-beta signaling in ECs recapitulate some of the cardinal features of retinal and neurologic diseases associated with vascular inflammation. These observations suggest that therapies that promote TGF-beta-dependent anti-inflammatory responses in ECs could represent a promising strategy for disease modulation.

neuroscience↗

bioRxiv2023

Bacterial meningitis in the early postnatal mouse studied at single-cell resolution

Bacterial meningitis is a major cause of morbidity and mortality, especially among infants and the elderly. Here we study mice to assess the response of each of the major meningeal cell types to early postnatal E. coli infection using single nucleus RNA sequencing (snRNAseq), immunostaining, and genetic and pharamacologic perturbations of immune cells and immune signaling. Flat mounts of the dissected arachnoid and dura were used to facilitiate high-quality confocal imaging and quantification of cell abundances and morphologies. Upon infection, the major meningeal cell types - including endothelial cells (ECs), macrophages, and fibroblasts - exhibit distinctive changes in their transcriptomes. Additionally, ECs in the arachnoid redistribute CLDN5 and PECAM1, and arachnoid capillaries exhibit foci with reduced blood-brain barrier integrity. The vascular response to infection appears to be largely driven by TLR4 signaling, as determined by the nearly identical response induced by LPS administration and by the blunted response to infection in Tlr4-/- mice.

immunology↗