PhD student Institute of Molecular Biotechnology GmbH Vienna, Wien, Austria
Abstract: Much of what is known about human cortical development has been derived from rodent models, due to the highly conserved neural types and processes. However, a unique feature of human brain development is the protracted period of neurogenesis and interneuron migration. In humans, recent findings in postmortem tissue of the Arc migratory stream, the arc-ACC, and the EC stream into the postnatal cortex have changed the dogma that cortical interneuron migration is complete before birth. These studies shed light on a prolonged stage of human brain development and a longer plasticity window for fine-tuning of the developing circuit with local inhibitory inputs. This also leaves a wider window for potential insults, leading to neurological disorders such as autism and epilepsy. Here we have derived an iPSC dorsal::ventral assembloid model with fusion at day 120 and analysis after up to 390 days of culture, to model the migration dynamics of this postnatal process. Interestingly, we observed after over 200 days that newly born migratory interneurons arrange themselves into connected chains that are surrounded by astrocytes, unlike the dispersed migration seen at earlier time points. These interneurons express caudal ganglionic eminence (CGE) markers and are born late, shown with EdU birth dating. Analysis by electron microscopy reveals an architecture essentially indistinguishable from what has been seen in early postnatal human brains. Using a combination of time-lapse imaging, mathematical modelling, and single cell spatial transcriptomics, we uncovered that this unique mode of migration requires both intrinsic cues from the late-born interneurons, as well as specific interactions between the interneurons and surrounding astrocytes for chain formation and migration. For the first time, our work reconstitutes events of human brain development that occur after birth, allowing a genetic and cell biological analysis of this important phenomenon.
