Halima Hannah Schede

Lipids are fundamental components of the brain, crucial for synaptic transmission and signal propagation. Altered brain lipid composition is associated with common and rare neuropathologies, yet the spatial organization of the mammalian brain lipidome remains insufficiently characterized compared with other modalities ^1–6 . Here we mapped the membrane-lipid architecture of the adult mouse brain at micrometric scale, across sexes and during pregnancy. This lipid brain atlas reveals that lipids describe a fine-grained biochemical structure that aligns with functional anatomy. Membrane-lipid spatial heterogeneity clusters into territories, which we termed ‘lipizones’. Lipizones partially mirror cell-type territories, but also capture distal axon terminals. Through lipizones, we (1) reveal the organizing principles of the grey matter lipidome, related to connectivity and cytoarchitecture; (2) discover a new axis of oligodendrocyte heterogeneity in the white matter; and (3) find biochemical zonation in the choroid plexus and in the ventricular walls. We show that this lipidomic architecture can adapt to changing physiological needs. In the brain of pregnant female mice, the white matter is metabolically activated and the cortex undergoes a lipizone-specific remodelling that is particularly pronounced in layer 4. These results are a foundational resource ( https://lbae-v2.epfl.ch/ ) poised to reshape the understanding of lipids in brain development, physiology and pathology.

Lipids are fundamental components of the brain, crucial for synaptic transmission and signal propagation. Altered brain lipid composition is associated with common and rare neuropathologies, yet, the spatial organization of the mammalian brain lipidome remains insufficiently characterized compared to other modalities. Here, we mapped the membrane lipid architecture of the adult mouse brain at micrometric scale, across sexes, and during pregnancy. This Lipid Brain Atlas reveals that lipids define a fine-grained biochemical structure that aligns with functional anatomy. Membrane lipid spatial heterogeneity clusters into territories, which we termed lipizones. Lipizones partially mirror cell type territories, but also capture distal axon terminals. Through lipizones, (i) we reveal the organizing principles of the gray matter lipidome, related to connectivity and cytoarchitecture; (ii) we discover a new axis of oligodendrocyte heterogeneity in the white matter; (iii) and we find biochemical zonation in the choroid plexus and in the ventricular walls. We show that this lipidomic architecture can adapt to changing physiological needs. In the brain of pregnant females, the white matter is metabolically activated and the outer cortex is reorganized. These results are a foundational resource (https://lbae-v2.epfl.ch/), poised to reshape our understanding of lipids in brain development, physiology, and pathology.

Embryo development entails the formation of anatomical structures with distinct biochemical compositions. Compared with the wealth of knowledge on gene regulation, our understanding of metabolic programs operating during embryogenesis is limited. Mass spectrometry imaging (MSI) has the potential to map the distribution of metabolites across embryo development. Here we established uMAIA, an analytical framework for the joint analysis of large MSI datasets, which enables the construction of multidimensional metabolomic atlases. Employing this framework, we mapped the four-dimensional (4D) distribution of over a hundred lipids at micrometric resolution in Danio rerio embryos. We discovered metabolic trajectories that unfold in concert with morphogenesis and revealed spatially organized biochemical coordination overlooked by bulk measurements. Interestingly, lipid mapping revealed unexpected distributions of sphingolipid and triglyceride species, suggesting their involvement in pattern establishment and organ development. Our approach empowers a new generation of whole-organism metabolomic atlases and enables the discovery of spatially organized metabolic circuits.

Embryo development entails the formation of anatomical structures with distinct biochemical compositions. Compared with the wealth of knowledge on gene regulation, our understanding of metabolic programs operating during embryogenesis is limited. Mass spectrometry imaging (MSI) has the potential to map the distribution of metabolites across embryo development. Here, we established an analytical framework for the joint analysis of large MSI datasets that allows for the construction of multi-dimensional metabolomic atlases. Employing this framework, we mapped the 4D distribution of over a hundred lipids at quasi-single-cell resolution in Danio rerio embryos. We discovered metabolic trajectories that unfold in concert with morphogenesis and revealed spatially organized biochemical coordination overlooked by bulk measurements. Interestingly, lipid mapping revealed unexpected distributions of sphingolipid and triglyceride species, suggesting their involvement in pattern establishment and organ development. Our approach empowers a new generation of whole-organism metabolomic atlases and enables the discovery of spatially organized metabolic circuits.

Condensation by phase separation has recently emerged as a mechanism underlying many nuclear compartments essential for cellular functions. Nuclear condensates enrich nucleic acids and proteins, localize to specific genomic regions, and often promote gene expression. How diverse properties of nuclear condensates are shaped by gene organization and activity is poorly understood. Here, we develop a physics-based model to interrogate how spatially-varying transcription activity impacts condensate properties and dynamics. Our model predicts that spatial clustering of active genes can enable precise localization and de novo nucleation of condensates. Strong clustering and high activity results in aspherical condensate morphologies. Condensates can flow towards distant gene clusters and competition between multiple clusters lead to stretched morphologies and activity-dependent repositioning. Overall, our model predicts and recapitulates morphological and dynamical features of diverse nuclear condensates and offers a unified mechanistic framework to study the interplay between non-equilibrium processes, spatially-varying transcription, and multicomponent condensates in cell biology.