Chair: Bogna Badyra (Nencki Institute of Experimental Biology, PAS, Warsaw, Poland)

Symposium 8: Human Brain Development

This session aims to introduce congress participants to up-to-date techniques to study brain development in the human context. Invited speakers have exceptional expertise in brain organoids’ culture, genomic studies, and the complexity of mosaics of cells appearing during development. The presented data will also cover data about human fetal development.


Simona Lodato, Humanitas University, Milan, Italy

3D Human Organoids to Explore the Development of the Cerebral Cortex and Its Barrier

Cerebral cortex development is influenced by genetic, activity and environmental factors that shape neuronal diversity, synaptic connectivity, and network formation. Using cortical organoids, we model key developmental aspects, focusing on the emergence and modulation of spontaneous activity and circuit formation. This is relevant for understanding infantile epilepsy, where early activity patterns are altered. Combining multiomics and calcium imaging, we aim to uncover mechanisms underlying early epilepsies, to identify new therapies. We also investigate the role of the choroid plexus (ChP) and other barriers in supporting cortical maturation, activity, and network integration. To this end, we developed a ChP Org model that replicates the histological, functional, and ultrastructural features of native human ChP, able to respond to external stimuli.


Antonela Bonafina, University of Liège, Liège, Belgium

Cortical interneuron migration in the forebrain – An evo-devo perspective

The cerebral cortex contains excitatory projection neurons (PNs) and inhibitory interneurons (cINs). Most cINs originate in the ventral forebrain and migrate tangentially to integrate into cortical circuits. Prior research in mice showed that CCP1 (cytosolic carboxypeptidase 1) regulates cIN migration by deglutamylating myosin light chain kinase. Loss of CCP1 disrupts cIN migration, indirectly increasing PN generation and affecting cortical development. This study explores CCP1’s role in human cIN migration using primary human forebrain cultures and cerebral assembloids. Disrupting CCP1 expression impairs migration, altering the motion from saltatory to gliding. While CCP1 similarly regulates nucleokinesis in human and mouse cINs, human cINs uniquely experience disrupted leading process branching, indicating an evolved CCP1 function in human cIN migration.


Aleksandra Pękowska, Nencki Institute of Experimental Biology, PAS, Warsaw, Poland

Human astrocytes – evolution and link to neurodevelopmental diseases

Astrocytes are the gatekeepers of brain homeostasis. Yet, apart from the housekeeping functions, astrocytes regulate synapse formation, activity, and pruning – processes that underlie higher-level brain functions and are critical for brain evolution. Using in-vivo data and human, chimpanzee, and macaque induced pluripotent stem cell-derived astrocytes (iAstrocytes), we recently uncovered that the expression of intellectual disability-related genes including CTCF, a factor orchestrating the three-dimensional chromatin structure, is progressively downregulated in the human astrocyte evolution. However, the relevance of this process to brain development and evolution remains unclear. I will present data illustrating broad changes in the CTCF-mediated chromatin topology in primate astrocytes and link these changes to the development of the human nervous system. Likewise, I will highlight the contribution of aberrant chromatin structure in astrocytes to neuronal development.

References:
1. Ciuba K, et al. Molecular signature of primate astrocytes reveals pathways and regulatory changes contributing to the human brain evolution. bioRxiv, 2023. doi: 10.1016/j.stem.2024.12.011
2. Vian L, et al. The Energetics and Physiological Impact of Cohesin Extrusion. Cell, 2018. doi: 10.1016/j.cell.2018.03.072


Maciej Figiel, Institute of Bioorganic Chemistry, PAS, Poznań, Poland

Modelling neurodevelopmental pathogenesis of Huntington’s disease with human iPSC lines and brain organoids

Huntington’s disease (HD) is a polyglutamine neurodegenerative disease involving neurodevelopmental pathogenesis. We developed a new model, fused dorso-ventral forebrain organoids mimicking the affected brain regions in HD and exhibiting significant growth and altered gene expression, suggesting that cells in HD brains represent specific phenotypes that favor increased proliferation over differentiation. In the HD models, we observed a strong increase in the cellular population of choroid plexus occurring in the blood-brain barrier (BBB). In addition, the upregulation of the choroid plexus marker TTR in mouse embryos and blood serum suggests its potential significance in HD pathogenesis. Our findings, may facilitate early detection and monitoring of HD and could enable the development of novel HD therapies targeting the choroid plexus.

References:
1. Wiatr K, et al. Huntington Disease as a Neurodevelopmental Disorder and Early Signs of the Disease in Stem Cells. Mol Neurobiol., 2018. doi: 10.1007/s12035-017-0477-7
2. Świtońska-Kurkowska K, et al. Identification of neurodevelopmental organization of the cell populations of juvenile Huntington’s disease using dorso-ventral HD organoids and HD mouse embryos. bioRxiv, 2024. doi: 10.1101/2024.09.23.614496

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