Cerebral organoids to decipher molecular mechanisms perturbed in EML1 induced ribbon-like subcortical heterotopia

• Applicant: Dr. Julia Ladewig
• Subject Area: Developmental Neurobiology ; Developmental Biology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 448223086

During development the human brain has to form a complex neuronal network, which requires a precise choreography of neurogenesis, neuronal migration and synaptogenesis. Human malformations associated with defects in cortical development can result in cortical dis-organization with severe consequences including epilepsy and intellectual disability. Various mouse models have been used to study human malformations of cortical development (MCD), but they are limited by structural differences between the murine and the human brain. With the ability to generate induced pluripotent stem (iPS) cells and PS cell-derived organoids mimicking human-specific brain development in vitro in combination with the advent of efficient gene editing technologies and high throughput single cell transcriptional profiling we are now technologically equipped to decipher the molecular changes associated with the dysfunction of single genes leading to MCD in a human context. In the proposed project we aim to use cerebral organoids derived from patients and genome edited isogenic iPS cell pairs to address pathophysiological changes associated with ribbon-like subcortical heterotopia caused by mutations in the EML1-gene. This MCD is characterized by a megalencephaly with a very characteristic ribbon-like heterotopia (and an overlying polymicrogyria-like cortex) in the region of the outer SVZ, resembling a second inner cortex and our working hypothesis is that progenitors, especially in the human brain, may play a contributing role to the disease phenotype. Based on our preliminary data, which indicate that certain aspects of EML1-induced ribbon-like subcortical heterotopia can be recapitulated in organoids, we will perform a detailed analysis of the histoarchitecture, the behavior of progenitors and transcriptional profiling in organoids from above-mentioned iPS cells. Our analyses will include immunohistochemistry, cell tracing and transcriptional profiling at a single cell resolution. We expect that our forebrain-type cerebral organoid model for EML1 induced ribbon-like subcortical heterotopia will give us an in depth understanding of mechanisms perturbed during early human cortical development and the role of EML1 in particular.

• DFG Programme: Research Grants