Bajaj, Sunanjay; Bagley, Joshua A.; Sommer, Christoph MISTA; Vertesy, Abel; Nagumo Wong, Sakurako; Krenn, Veronica; Lévi-Strauss, Julie; Knoblich, Juergen A.
Inhibitory GABAergic interneurons migrate over long distances from their extracortical origin into the developing cortex. In humans, this process is uniquely slow and prolonged, and it is unclear whether guidance cues unique to humans govern the various phases of this complex developmental process. Here, we use fused cerebral organoids to identify key roles of neurotransmitter signaling pathways in guiding the migratory behavior of human cortical interneurons. We use scRNAseq to reveal expression of GABA, glutamate, glycine, and serotonin receptors along distinct maturation trajectories across interneuron migration. We develop an image analysis software package, TrackPal, to simultaneously assess 48 parameters for entire migration tracks of individual cells. By chemical screening, we show that different modes of interneuron migration depend on distinct neurotransmitter signaling pathways, linking transcriptional maturation of interneurons with their migratory behavior. Altogether, our study provides a comprehensive quantitative analysis of human interneuron migration and its functional modulation by neurotransmitter signaling.
We thank all Knoblich laboratory members for continued support and discussions. We thank the IMP/IMBA BioOptics facility, particularly Pawel Pasierbek, Alberto Moreno Cencerrado and Gerald Schmauss, the IMP/IMBA Molecular Biology Service, in particular Robert Heinen, the IMP Bioinformatics facility, in particular Thomas Burkard, the Vienna Biocenter Core Facilities (VBCF) Histopathology facility, in particular Tamara Engelmaier, and the VBCF Next Generation Sequencing Facility, notably Volodymyr Shubchynskyy and Carmen Czepe. We would also like to thank Simon Haendeler for advice on statistical analyses, Jose Guzman for discussions and assistance with slice culture setups, Oliver L. Eichmueller for discussions and assistance with microscopy, and E.H. Gustafson, S. Wolfinger, and D. Reumann for technical assistance regarding generation of cerebral organoids. This project received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie fellowship agreement Nr.707109 awarded to J.A.B. Work in J.A.K.'s laboratory is supported by the Austrian Federal Ministry of Education, Science and Research, the Austrian Academy of Sciences, the City of Vienna, a Research Program of the Austrian Science Fund FWF (SFBF78 Stem Cell, F 7803-B) and a European Research Council (ERC) Advanced Grant under the European 20 Union’s Horizon 2020 program (grant agreement no. 695642).
Bajaj S, Bagley JA, Sommer CM, et al. Neurotransmitter signaling regulates distinct phases of multimodal human interneuron migration. EMBO Journal. 2021;40(23). doi:10.15252/embj.2021108714
Bajaj, S., Bagley, J. A., Sommer, C. M., Vertesy, A., Nagumo Wong, S., Krenn, V., … Knoblich, J. A. (2021). Neurotransmitter signaling regulates distinct phases of multimodal human interneuron migration. EMBO Journal. Embo Press. https://doi.org/10.15252/embj.2021108714
Bajaj, Sunanjay, Joshua A. Bagley, Christoph M Sommer, Abel Vertesy, Sakurako Nagumo Wong, Veronica Krenn, Julie Lévi-Strauss, and Juergen A. Knoblich. “Neurotransmitter Signaling Regulates Distinct Phases of Multimodal Human Interneuron Migration.” EMBO Journal. Embo Press, 2021. https://doi.org/10.15252/embj.2021108714.
S. Bajaj et al., “Neurotransmitter signaling regulates distinct phases of multimodal human interneuron migration,” EMBO Journal, vol. 40, no. 23. Embo Press, 2021.
Bajaj S, Bagley JA, Sommer CM, Vertesy A, Nagumo Wong S, Krenn V, Lévi-Strauss J, Knoblich JA. 2021. Neurotransmitter signaling regulates distinct phases of multimodal human interneuron migration. EMBO Journal. 40(23), e108714.
Bajaj, Sunanjay, et al. “Neurotransmitter Signaling Regulates Distinct Phases of Multimodal Human Interneuron Migration.” EMBO Journal, vol. 40, no. 23, e108714, Embo Press, 2021, doi:10.15252/embj.2021108714.
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