Biology subjects

Thomsen, J. S.

Publications and source records attributed to Thomsen, J. S..

4 recordsLinked to original sources

bioRxiv2026

Macrophage calcium signaling dynamics revealed using genetically-encoded sensors

Macrophages (M{Phi}s) inhabit all mammalian organs, adapting to and influencing the tissues in which they reside. These versatile cells rapidly respond to tissue-specific signals, clean up debris and serve as the first line of defense against pathogens. Their ability to act quickly relates to their abundance and specific arrangement in tissues, as well as the systems they possess for detecting, processing and integrating emergent signals. Ca2+ is a fast second messenger that has been linked to many of the core functions of M{Phi}s. However, spatiotemporal features of physiologically-relevant Ca2+ signals in M{Phi}s remain largely uncharacterized. Using mouse models expressing genetic biosensors and fluorescently tagged channels, we visualize M{Phi} Ca2+ signal dynamics and heterogeneity, uncover a remarkable degree of mechanosensitivity in these cells, and characterize the physiological consequences of genetic ablation of Piezo1 channels via analysis of knockout models across their lifetime. Our in-depth investigation of M{Phi} Ca2+ signaling dynamics has broad relevance for the field of M{Phi} biology and the tissues that these cells support.

immunology↗

bioRxiv2025

Genetic rescue of pathogenic O-GlcNAc dyshomeostasis associated with microcephaly and motor deficits

Missense variants in O-GlcNAc transferase (OGT) result in OGT congenital disorder of glycosylation (OGT-CDG), an intellectual disability syndrome associated with O-GlcNAc dyshomeostasis and a range of neurodevelopmental defects. Inhibition of O-GlcNAcase (OGA), the enzyme responsible for removing protein O-GlcNAcylation, has been explored as a target for modulating brain O-GlcNAc homeostasis in neurodegenerative diseases and may also be a target for OGT-CDG. Here, we describe an OGT-CDG mouse line that exhibits microcephaly, motor deficits, and brain O-GlcNAc dyshomeostasis, closely mirroring patient symptoms. We genetically explored OGA as a target for OGT-CDG by crossing these mice with a line carrying catalytically inactive OGA. Encouragingly, this partially restored O-GlcNAc homeostasis in brain and blood, although it did not result in significant phenotypic rescue. These findings suggest that OGA inhibition can modulate enzymatic imbalance in OGT-CDG mice, and that blood can be used to monitor the effects of interventions targeting O-GlcNAc dyshomeostasis.

neuroscience↗

bioRxiv2025

Pathogenic O-GlcNAc dyshomeostasis associated with cortical malformations and hyperactivity

Missense variants in the O-GlcNAc transferase (OGT) gene have recently been shown to segregate with a syndromic form of intellectual disability (OGT-ID), underscoring the importance of protein O-GlcNAcylation in brain function. However, the underlying pathophysiological mechanisms linking ID to potential OGT malfunction--whether developmental, neurophysiological, or both--remain unclear. Here, we present comprehensive analyses encompassing behaviour and brain architecture of a rodent model carrying the pathogenic C921Y OGT-ID variant. These mice show a range of behavioural deficits, including hyperactivity, impulsivity, and associative learning phenotypes. Structural studies, using micro-computed tomography and magnetic resonance imaging, revealed reduced skull size, microcephaly, reduced cortical thickness and hypoplastic corpus callosum. Detailed histological analyses revealed dysplastic changes in the neocortex, predominantly affecting the superficial layers of cingulate cortex. Mechanistically, quantitative proteomic analyses revealed O-GlcNAc dyshomeostasis associated with distinct perturbed molecular pathways involved in brain development. Taken together, these data reveal neurodevelopmental defects associated with O-GlcNAc dyshomeostasis and provide a platform for dissecting mechanism and treatments of OGT-ID.

neuroscience↗

bioRxiv2024

Restoring oxidative phosphorylation enhances osteogenesis in mitochondrial DNA translation defective human bone marrow stromal cells

Bone formation is critical to maintain bone integrity. Here, we studied the importance of intact energy metabolism for bone formation in humans. The skeletal impact of impaired oxidative phosphorylation (OXPHOS) was investigated in adult individuals with genetically defective mitochondrial DNA translation (m.3243A>G). Although impaired mitochondrial ATP production in m.3243A>G human bone marrow stromal cells (hBMSC) was compensated by increased glycolytic ATP production (unchanged net ATP production), both in vitro osteoblast differentiation and in vivo ectopic bone formation were decreased. The impaired OXPHOS was associated with mitochondrial stress and disruption of the pro-osteogenic transcriptional program characteristic of hBMSC. Supporting OXPHOS pharmacologically in hBMSC restored mitochondrial ATP production, their transcriptional program and metabolism, leading to upregulation of osteogenic genes and restoration of bone formation capacity. These findings demonstrate a mitochondrial regulation mechanism of the osteogenic capacity of hBMSCs and identify OXPHOS as a potential target for increasing bone formation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/629993v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@fca817org.highwire.dtl.DTLVardef@17fb2d3org.highwire.dtl.DTLVardef@b5667forg.highwire.dtl.DTLVardef@15c35db_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗