Biology subjects

Kastner, P.

Publications and source records attributed to Kastner, P..

3 recordsLinked to original sources

bioRxiv2026

Evolutionary rewiring of the DNM2 proline-rich domain drives lineage-specific constraints in erythropoiesis

Dynamin-2 (DNM2) is a ubiquitously expressed GTPase essential for membrane trafficking, yet how its evolution shapes tissue-specific functions remains unclear. Here, we generated a humanized mouse model in which murine Dnm2 is fully replaced by human DNM2. Human DNM2 rescues the embryonic lethality of Dnm2 deletion but cannot sustain postnatal hematopoiesis, leading to fatal hemolytic anemia, erythroblast maturation arrest, reticulocytosis, and macrothrombocytosis. The defect emerges selectively during postnatal bone marrow erythropoiesis and is associated with impaired transferrin receptor turnover, despite normal fetal liver hematopoiesis. Comparative proteomics reveals extensive species-specific rewiring of the DNM2 proline-rich domain (PRD) interactome, with GRB2 as the sole conserved partner. Dnm2 haploinsufficiency phenocopies the erythroid defect with reduced severity, indicating a dosage-sensitive loss-of-function mechanism. These findings identify PRDs as rapidly evolving context-dependent adaptors that tune ubiquitous proteins to tissue-specific demands, and highlight regulatory domains compatibility as a key consideration for humanized models and gene-replacement strategies.

genetics↗

bioRxiv2025

How Ikaros and Aiolos homo- and heterodimers drive gene expression to ensure B cell development

Ikaros family transcription factors (TF) are major regulators of cell differentiation and function. They function as homo- and heterodimers, but the contribution of specific dimers to gene regulation is unknown. We investigated the function of Ikaros-Ikaros, Ikaros-Aiolos and Aiolos-Aiolos in B cell development, and show that the dimers are not equivalent. Ikaros homodimers are required in proB and large preB cells where they bind and regulate the expression of a surprisingly small number of genes related to cell adhesion and migration, predominantly as transcriptional repressors. In contrast, Ikaros-Aiolos heterodimers and Aiolos homodimers are required in small preB and immature IgM+ B cells to regulate 10-fold larger target gene repertoires involved in B cell receptor signaling and immune functions. Aiolos-containing dimers act mainly as repressors in small preB cells but activators in immature B cells, where Aiolos-Aiolos antagonizes Ikaros-Ikaros. Mechanistically, Aiolos binds more GGAA motifs with different flanking nucleotides than Ikaros, which depends on a single amino acid difference in zinc finger 3 of its DNA binding domain. These results illustrate how homo- and heterodimerization of homologous TF proteins can markedly impact binding specificity, target gene response and pathway modulation in cells of the same lineage.

immunology↗

bioRxiv2024

Integrated single-cell atlas of human atherosclerotic plaques

Atherosclerosis, a major cause of cardiovascular diseases, is characterized by the buildup of lipids and chronic inflammation in the arteries, leading to plaque formation and potential rupture. The underlying causal immune mechanisms and alterations in structural cell composition and plasticity driving plaque progression remain incompletely defined. Recent advances in single-cell transcriptomics (scRNA-seq) have provided deeper insights into the roles of immune and non-immune cells in atherosclerosis. However, existing public scRNA-seq datasets often lack comprehensive cell type coverage and consistent annotations, posing challenges for downstream analyses. In this study, we present an integrated single-cell atlas of human atherosclerotic plaques, encompassing 261,747 high-quality annotated cells from carotid, coronary, and femoral arteries. By benchmarking and applying the best-performing data integration method, scPoli, we achieved robust cell type annotations validated by expert consensus and surface protein measurements. This comprehensive atlas enables accurate automatic cell type annotation of new datasets, optimal experimental design, and deconvolution of existing as well as novel bulk RNA-seq data to comprehensively determine cell type proportions in human atherosclerotic lesions. It facilitates future studies by providing an interactive WebUI for easy data annotation and experimental design, while supporting various downstream applications, including integration of genetic association studies and experimental planning.

cell biology↗