2026 ECNP Congress

PS04-4151

Altered extracellular vesicle microRNAs in LGALS3BP mutant cerebral organoids: implications for cortical development

Andrea Forero — D. Rodrigues Pereira, K. Christofi, K. Tuntevski, D. De Pietri Tonelli, M. Myoga, S. Cappello · Ludwig Maximilian University of Munich, Division of Physiological Genomics, Munich, Germany

2026 ECNP Congress

Neurodevelopmental disorders are highly polygenic conditions associated with widespread clinical heterogeneity, making diagnosis reliant primarily on behavioural assessment. This highlights the urgent need for objective biological readouts that can support earlier and more precise diagnosis. In recent years, extracellular vesicles (EVs) have emerged as promising candidates for biomarker discovery in neurodevelopmental and neuropsychiatric conditions [1]. EVs are secreted membrane-bound nanoparticles that mediate intercellular communication by transporting nucleic acids, lipids, and proteins between cells. Because their molecular cargo reflects the identity and physiological state of their cell of origin, EVs offer a unique window into otherwise inaccessible tissues such as the developing brain. Furthermore, treatment with healthy control EVs can ameliorate disease-associated phenotypes in mouse and in vitro model systems, pointing to their therapeutic potential [2][3]. This is likely due to the capacity of EVs to modulate key developmental processes such as cell fate acquisition, neuronal differentiation and synaptic function [4][5]. This growing clinical interest in EVs emphasizes the need for translational studies that provide a better understanding of EV biogenesis, cargo selection, and functional impact in the context of neurodevelopmental disorders. While the protein content of EVs has been more extensively characterized, a crucial class of EV cargo remains comparatively unexplored: microRNAs (miRNAs). These small non-coding RNAs regulate gene expression at the post-transcriptional level and are well-positioned to orchestrate complex developmental programs. The aim of this work is to study transcriptional regulation via EV-miRNAs in cortical development by leveraging human induced pluripotent stem cell (iPSC)-derived 2D neural cultures and cerebral organoids. Our results identified miRNAs enriched in EVs from neural progenitor cells, neurons and astrocytes, as well as from cerebral organoids patterned to resemble the dorsal and ventral telencephalon. These results emphasize the cell-type and brain-region specificity of EV-miRNA signatures, with the potential to target discrete neurodevelopmental processes including neurogenesis, synaptogenesis and axonal regeneration. Furthermore, we sequenced the EV miRNome of cerebral organoids carrying a mutation in LGALS3BP, a gene coding for Galectin-3-binding protein, whose mutation leads to cortical malformation, autism spectrum disorder and seizures. We observed the dysregulation of well-conserved miRNAs, such as miR-9 and miR-200c, and more interestingly, novel primate-specific miRNAs. The overexpression of these primate-specific miRNAs in our neural model systems led to both cell-autonomous and non-cell-autonomous physiological alterations in neurite outgrowth, neuronal migration and progenitor proliferation. Furthermore, by combining a patch-based collection technique with single-cell RNA sequencing, we detected transcriptomic changes that may be mediating the phenotypic alterations observed. Overall, our results highlight the previously unrecognized contribution of EV-associated miRNAs to the regulation of human cortical development and suggest that their dysregulation may represent a key, human-relevant mechanism underlying neurodevelopmental disease pathology. Furthermore, these findings support future development of EV-based diagnostics and targeted RNA therapeutics as they can serve as a reference for identifying brain-enriched and disease-associated markers in neurodevelopmental disorders.

References

  1. Ünal, D. & Sarıköse Özgüven, A. Exosomes: New biomarker and therapeutic candidates in autism spectrum disorder research. Acta Neuropsychiatrica vol. 38 Preprint at https://doi.org/10.1017/neu.2025.10047 (2025).
  2. Perets, N., Oron, O., Herman, S., Elliott, E. & Offen, D. Exosomes derived from mesenchymal stem cells improved core symptoms of genetically modified mouse model of autism Shank3B. Mol. Autism 11, (2020).
  3. Choudhary, A. et al. Extracellular vesicles from stem cells rescue cellular phenotypes and behavioral deficits in SHANK3-associated ASD neuronal and mouse models. Cell Death Dis. 17, 244 (2026).
  4. Sharma, P. et al. Exosomes regulate neurogenesis and circuit assembly. Proc. Natl. Acad. Sci. U. S. A. 116, 16086–16094 (2019).
  5. Forero, A., Pipicelli, F., et al. Extracellular vesicle-mediated trafficking of molecular cues during human brain development. Cell Rep. 43, (2024).