Biology subjects

Mirabella, F.

Publications and source records attributed to Mirabella, F..

5 recordsLinked to original sources

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↗

bioRxiv2025

Benchmarking cerebellar organoids to model autism spectrum disorder and human brain evolution

While cortical organoids have been used to model different facets of neurodevelopmental conditions and human brain evolution, cerebellar organoids have not yet featured so prominently in the same context, despite increasing evidence of this brain regions importance for cognition and behavior. Here, we provide a longitudinal characterization of cerebellar organoids benchmarked against human fetal data and identify at very early stages of development a significant number of dynamically expressed genes relevant for neurodevelopmental conditions such as autism and attention deficit hyperactivity disorders. Then, we model an ASD mutation impacting CHD8, showing both granule cell and oligodendrocyte lineages prominently affected, resulting in altered network activity in more mature organoids. Lastly, using CRISPR/Cas9 editing, we also model an evolution-relevant mutation in a regulatory region of the CADPS2 gene. We investigate the effect of the derived allele exclusive to Homo sapiens, identifying a rerouting of the CADPS2-expression in rhombic lip cells, coupled with a different sensitivity to hypoxia which in turn lead to a differential timing of granule cell differentiation. HIGHLIGHTSO_LILongitudinal characterization of cerebellar organoids uncovers disorder related genes especially at early stages of development C_LIO_LIMutation in CHD8 alter rhombic lip and oligodendrocytes differentiation via WNT pathway C_LIO_LIRerouting of CADPS2 expression, delaying differentiation and migration, in recent human evolution C_LI IN BRIEFAprile and colleagues longitudinally profiled cerebellar organoids, benchmarking them against a fetal human atlas and identified a highly dynamic expression of genes related to cognitive and behavioral disorders especially at early stages of differentiation. Organoids were used to model the impact of a high-penetrance mutation associated with autism spectrum disorder and a high-frequency derived allele in Homo sapiens predicted to have played a role in recent brain evolution.

neuroscience↗

bioRxiv2025

Glioblastoma stem cell morphotypes convey distinct cell states and clinically relevant functions

Glioblastoma (GBM) is an aggressive brain tumor and an unmet clinical need due to its invasiveness and therapy-resistance. These features are driven by glioblastoma stem cells (GSCs), which exhibit remarkable functional heterogeneity. However, GSC transcriptional profiling alone cannot predict clinically relevant behaviors. Here, we developed CellShape-seq, a spatial transcriptomics platform that integrates cell morphology with transcriptome. This identified three GSC morphoclasses corresponding to distinct transcriptomic states and functions: (1) nonpolar cells show differentiation and therapy sensitivity, (2) elongated cells are invasive, and (3) multipolar cells form intercellular networks. Importantly, chemoresistance is morphoclass-specific: elongated GSCs depend on YAP/TEAD1 signaling, while multipolar GSCs rely on gap junction-mediated networks. Targeting these vulnerabilities with specific inhibitors sensitized resistant GSC morphoclasses to temozolomide (TMZ) in patient-derived organoids. Our findings demonstrate that morphology provides critical insights into GSC behavior and establish a rationale for morphology-informed therapies to overcome resistance and improve outcomes in GBM. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=85 SRC="FIGDIR/small/644884v2_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@141e698org.highwire.dtl.DTLVardef@18a238corg.highwire.dtl.DTLVardef@23ef62org.highwire.dtl.DTLVardef@1390c07_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2020

Transient Maternal IL-6 boosts glutamatergic synapses and disrupts hippocampal connectivity in the offspring

Early prenatal inflammatory conditions are thought to represent a risk factor for different neurodevelopmental disorders, with long-term consequences on adult brain connectivity. Here we show that a transient IL-6 elevation, occurring at vulnerable stages of early neurodevelopment, directly impacts brain developmental trajectories through the aberrant enhancement of glutamatergic synapses and overall brain hyper-connectivity. The IL6-mediated boost of excitatory synapse density results from the neuron-autonomous, genomic effect of the transcription factor STAT3 and causally involves the activation of RGS4 gene as a candidate downstream target. The STAT3/RGS4 pathway is also activated in neonatal brains as a consequence of maternal immune activation protocols mimicking a viral infection during pregnancy. By demonstrating that prenatal IL-6 elevations result in aberrant synaptic and brain connectivity through the molecular players identified, we provide a mechanistic framework for the association between prenatal inflammatory events and brain neurodevelopmental disorders.

neuroscience↗

bioRxiv2020

The enhancement of activity rescues the establishment of Mecp2 null neuronal phenotypes

Mecp2 deficiency, the gene responsible for Rett syndrome (RTT), affects brain maturation by impairing neuronal activity, transcription and morphology. These three elements are physiologically linked in a feed-forward cycle where neuronal activity modulates transcription and morphology to further increase network maturity. We hypothesized that the reduced activity displayed by maturing Mecp2 null neurons during development could perturb such cycle, sustaining an improper transcriptional program that, ultimately, impairs neuronal maturation. Accordingly, we show that by enhancing activity within an early time window, Ampakine redirects, in vitro, the development of null neuronal networks towards more physiological routes. Similarly, the administration of the drug to newborn null offspring delays the progression of symptoms, significantly prolonging life span. Our data highlights the role of altered neuronal activity during the establishment of Mecp2 null networks and the importance of such early defects to the typically poor maturity of RTT brain functions in adulthood. We propose the existence of an "early molecular phase" of Rett syndrome, a detailed description of which might disclose relevant targets for new rescue treatments.

neuroscience↗