Biology subjects

Galbavy, W.

Publications and source records attributed to Galbavy, W..

5 recordsLinked to original sources

bioRxiv2026

Multiomics profiling of APECED peripheral blood highlights compositional increases in alternatively activated B cell subsets

APECED (Autoimmune PolyEndocrinopathy Candidiasis Ectodermal Dystrophy) is a rare syndrome of multi-organ autoimmunity driven by the presence of self-reactive T cells and autoantibodies caused by mutations in the gene Autoimmune regulator (AIRE). Compared to the well-defined role of AIRE in establishing and maintaining T cell central tolerance, less is known about how AIRE deficiency impacts B cell phenotypes that may contribute to a breakdown in peripheral B cell tolerance. Here we analyzed serum and peripheral blood cells from APECED patients and healthy donors using autoantibody profiling, proteomics, flow cytometry, scRNAseq based subset analysis, BCRseq, and autoantigen binding assays finding significant changes to the APECED B cell compartment. We show that while Naive and Transitional B cells are reduced, alternatively activated B cell subsets are expanded in APECED patients including IgM CD27+ and class switched Atypical B cells which exhibit BCR chain features prone to autoreactivity. Antibodies derived from either APECED or Healthy class switched atypical B cells bind autoantigens at significantly higher rates than control IgG B cells. Serum autoantibodies and proteomics highlight APECED common and patient variable changes. These results together show that APECED causes a compositional shift towards subsets that may promote broken B cell tolerance and autoimmunity.

immunology↗

bioRxiv2024

Orderly specification and precise laminar deployment of cortical glutamatergic projection neuron types through intermediate progenitors

The cerebral cortex comprises diverse types of glutamatergic projection neurons (PNs) generated from radial glial progenitors (RGs) through either direct neurogenesis or indirect neurogenesis (iNG) via intermediate progenitors (IPs). A foundational concept in corticogenesis is the "inside-out" model whereby successive generations of PNs sequentially migrate to deep then progressively more superficial layers, but its biological significance remains unclear; and the role of iNG in this process is unknown. Using genetic strategies linking PN birth-dating to projection mapping in mice, we found that the laminar deployment of IP-derived PNs substantially deviate from an inside-out rule: PNs destined to non-consecutive layers are generated at the same time, and different PN types of the same layer are generated at non-contiguous times. The overarching scheme of iNG is the sequential specification and precise laminar deployment of projection-defined PN types, which may contribute to the orderly assembly of cortical output channels and processing streams. HIGHLIGHTS- Each IP is fate-restricted to generate a pair of near-identical PNs - Corticogenesis involves the orderly generation of fate-restricted IP temporal cohorts - IP temporal cohorts sequentially as well as concurrently specify multiple PN types - The deployment of PN types to specific layers does not follow an inside-out order

neuroscience↗

bioRxiv2022

Direct and indirect neurogenesis generate a mosaic of distinct glutamatergic projection neuron types and cortical subnetworks

Variations in size and complexity of the cerebral cortex result from differences in neuron number and composition, which are rooted in evolutionary changes in direct and indirect neurogenesis (dNG and iNG) mediated by radial glial progenitors and intermediate progenitors, respectively. How dNG and iNG differentially contribute to cortical neuronal number, diversity, and connectivity are unknown. Establishing a genetic fate-mapping method to differentially visualize dNG and iNG in mice, we found that while both dNG and iNG contribute to all cortical structures, iNG contributes the largest relative proportions to the hippocampus and neocortex compared to insular and piriform cortex, claustrum, and the pallial amygdala. Within the neocortex, whereas dNG generates all major glutamatergic projection neuron (PN) classes, iNG differentially amplifies and diversifies PNs within each class; the two neurogenic pathways generate distinct PN types and assemble fine mosaics of lineage-based cortical subnetworks. Our results establish a ground-level lineage framework for understanding cortical development and evolution by linking foundational progenitor types and neurogenic pathways to PN types. Highlights- A genetic strategy for differential visualization of direct and indirect neurogenesis in the same animal. - dNG and iNG differentially contribute to piriform cortex, basolateral amygdala, hippocampus, and neocortex - Whereas dNG generates all major PN classes, iNG differentially amplifies and diversifies PNs within each class - dNG and iNG construct distinct cortical projection subnetworks.

neuroscience↗

bioRxiv2020

Cellular Anatomy of the Mouse Primary Motor Cortex

An essential step toward understanding brain function is to establish a cellular-resolution structural framework upon which multi-scale and multi-modal information spanning molecules, cells, circuits and systems can be integrated and interpreted. Here, through a collaborative effort from the Brain Initiative Cell Census Network (BICCN), we derive a comprehensive cell type-based description of one brain structure - the primary motor cortex upper limb area (MOp-ul) of the mouse. Applying state-of-the-art labeling, imaging, computational, and neuroinformatics tools, we delineated the MOp-ul within the Mouse Brain 3D Common Coordinate Framework (CCF). We defined over two dozen MOp-ul projection neuron (PN) types by their anterograde targets; the spatial distribution of their somata defines 11 cortical sublayers, a significant refinement of the classic notion of cortical laminar organization. We further combine multiple complementary tracing methods (classic tract tracing, cell type-based anterograde, retrograde, and transsynaptic viral tracing, high-throughput BARseq, and complete single cell reconstruction) to systematically chart cell type-based MOp input-output streams. As PNs link distant brain regions at synapses as well as host cellular gene expression, our construction of a PN type resolution MOp-ul wiring diagram will facilitate an integrated analysis of motor control circuitry across the molecular, cellular, and systems levels. This work further provides a roadmap towards a cellular resolution description of mammalian brain architecture.

neuroscience↗

bioRxiv2020

Genetic dissection of glutamatergic neuron subpopulations and developmental trajectories in the cerebral cortex

Diverse types of glutamatergic pyramidal neurons (PyNs) mediate the myriad processing streams and output channels of the cerebral cortex, yet all derive from neural progenitors of the embryonic dorsal telencephalon. Here, we establish genetic strategies and tools for dissecting and fate mapping PyN subpopulations based on their developmental and molecular programs. We leverage key transcription factors and effector genes to systematically target the temporal patterning programs in progenitors and differentiation programs in postmitotic neurons. We generated over a dozen temporally inducible mouse Cre and Flp knock-in driver lines to enable combinatorial targeting of major progenitor types and projection classes. Intersectional converter lines confer viral access to specific subsets defined by developmental origin, marker expression, anatomical location and projection targets. These strategies establish an experimental framework for understanding the hierarchical organization and developmental trajectory of PyN subpopulations that assemble cortical processing networks and output channels.

neuroscience↗