Biology subjects

Rava, V.

Publications and source records attributed to Rava, V..

3 recordsLinked to original sources

bioRxiv2026

COG5-mediated Golgi organization coordinates neural progenitor fate during human brain development

Apical radial glial cells (aRGs) are highly polarized epithelial cells that drive human cortical development through tightly regulated lineage progression. A distinctive feature of aRGs is their non-canonical Golgi organization, raising the possibility that specialized intracellular trafficking and secretory processes contribute to progenitor behaviour. However, how Golgi architecture contributes to human corticogenesis remains poorly understood. Here, we investigate this question in the context of COG5 deficiency, a rare congenital disorder of glycosylation associated with neurodevelopmental defects, using patient-derived fibroblasts and brain organoids, N-glycomics, glycolipidomics, and single-cell transcriptomics. We show that COG5 deficiency disrupts Golgi organization and impairs Golgi-to-ER retrograde trafficking. At the neurodevelopmental level, COG5-deficient organoids display altered ventricular organization and reduced basal progenitor abundance. Single-cell transcriptomic analysis reveals rewired developmental trajectories characterized by premature differentiation from apical progenitors with activation of neuronal pathways. Despite the absence of major abnormalities in plasma glycoproteins glycosylation, glycolipidomic analysis identified marked defects in glycosphingolipid maturation within patient-derived brain organoids, indicating selective impairment of neural lipid glycosylation. Transcriptomic and biochemical analyses further revealed dysregulation of developmental pathways, including reduced Notch signalling and altered localization of both cleaved Notch1 and the Golgi-associated protein ACBD3. Consistent with impaired progenitor maintenance, COG5-deficient organoids displayed altered cleavage plane orientation in apical progenitors. Together, our findings suggest a link between Golgi organization, intracellular trafficking, membrane glycosylation, and lineage progression in human neural progenitors, identifying Golgi architecture as an important regulator of apical radial glial cell biology and cortical development.

cell biology↗

bioRxiv2026

Evolutionary diversification of lipid logistics shapes synaptic maturation in primates

The prolonged developmental trajectory of the human brain (neoteny) is a defining feature of human evolution. Yet, the cellular mechanisms underlying this delay remain poorly understood. Here, comparing human and chimpanzee induced neurons and cerebral organoids, we we show that human neurons form fewer excitatory synapses and synchronize network activity later. Electron microscopy further revealed reduced synaptic vesicle docking and clustering near release sites, identifying altered presynaptic assembly as a prominent feature of human neuronal development. Unexpectedly, human neurons accumulate more, not less, membrane lipids, revealing a dissociation between lipid abundance and synaptic maturation. Transcriptomics and synaptosome proteomics resolve this paradox: chimpanzee neurons preferentially engage lipid metabolism and synaptic-maturation programs, whereas human neurons upregulate intracellular lipid transport and trafficking pathways. Together, our findings identify membrane organization as a previously unrecognized regulatory layer that controls neuronal neoteny. These results also suggest that evolutionary divergence can arise through changes in the spatial deployment of membrane lipids rather than their abundance, providing a molecular framework for understanding the evolution of human brain neoteny.

evolutionary biology↗

bioRxiv2026

Primate Astrocyte Evolution Controls the Tempo of Neuronal Development

Prolonged neuronal maturation, also referred to as neoteny, constitutes a hallmark of human brain evolution. Yet, the mechanisms controlling neotenic brain development remain poorly understood, and have been defined as neuron-intrinsic. Astrocytes shape synapse formation, activity, and elimination, and have changed substantially between humans and other species. Yet, whether the evolutionary divergence in astrocytes shapes the timing of neuronal maturation is unknown. Here, we show that astrocytes from humans and their closest living relatives, chimpanzees, exert contrasting effects on neuronal maturation: chimpanzee astrocytes accelerate it, whereas human astrocytes delay it, without affecting neuronal survival. Through comparative transcriptomics and epigenomics, we find that evolutionarily reduced APOE expression in human astrocytes underlies the observed delay in neuronal maturation: restoring APOE levels in human astrocytes accelerates neuronal development. We further establish that the Hippo-TEAD signaling represses APOE expression in human astrocytes, revealing a link between the enhanced morphological complexity of human astrocytes and the observed reduced tempo of neuronal development in their presence. Strikingly, neuronal genes differentially impacted by human and chimpanzee astrocytes are associated with schizophrenia, Alzheimers disease, and epilepsy, linking astrocyte evolution to disease vulnerability. Altogether, these findings establish that brain neoteny is partly a glial phenomenon, revealing that understanding the pace of human brain development requires understanding how astrocytes, not only neurons, have evolved.

neuroscience↗