Uncovering the role of the extracellular environment and its interplay with epigenetic regulation in human brain development

• Applicant: Professorin Dr. Mareike Albert
• Subject Area: Developmental Neurobiology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 567028671

The human brain, especially the cerebral cortex, is significantly more developed than that of other mammals and plays an essential role in complex, higher-dimensional functions. Yet, much is still unknown about the mechanisms by which its structure is formed. Mammalian neurogenesis and brain development have been studied using mouse models, and it has recently become clear that there are many differences in the process of brain formation between humans and mice. In particular, basal progenitor cells with a variety of morphologies and a longer duration of neural cell production characterize human cortical development. This joint Korean-German proposal aims to elucidate the role of the extracellular environment and its interplay with epigenetic regulation in human brain development. Capitalizing on the complementary expertise of the partner groups in extracellular matrix organisation and tissue stiffness (Korean partner) and epigenetic mechanisms (German partner), this project aims to explore a novel hypothesis of a feedback loop between both regulatory mechanisms using advanced 3D human brain organoid models. The regulation of stem cell differentiation via mechanotransduction has been proposed, but little is known about its significance in brain development and neural differentiation. In this study, we will focus on the link between the extracellular environment, specifically the composition of the extracellular matrix (ECM), and epigenetic mechanisms in the human developing neocortex. We will integrate ECM expression and epigenetic regulation using multi-omics data, combining data sets from the German and Korean partners, followed by molecular functional analysis. Furthermore, we will analyse changes in tissue stiffness caused by the manipulation of the ECM and the epigenome using brain organoids and atomic force microscopy. In addition, we will analyse changes in ECM composition and tissue stiffness in human organoid models of neurodevelopmental disorders caused by mutations in epigenetic factors. As a novel hypothesis, we will pursue feedback regulatory mechanisms between ECM expression and epigenetic regulation. Using both partners' unique expertise, we will elucidate multiple aspects of the regulation of human neural differentiation by the extracellular environment in human brain organoid models.

• DFG Programme: Research Grants
• International Connection: South Korea
• Partner Organisation: National Research Foundation of Korea, NRF
• Cooperation Partner: Professor Dr. Yoichi Kosodo