The mammalian neocortex is composed of diverse neuronal and glial cell classes that broadly arrange in six distinct laminae. Cortical layers emerge during development and defects in the developmental programs that orchestrate cortical lamination are associated with neurodevelopmental diseases. The developmental principle of cortical layer formation is based on concerted radial projection neuron migration, from their birthplace to their final target position. Radial migration occurs in defined sequential steps that are regulated by a large array of signaling pathways. However, based on genetic loss-of-function experiments, most studies have thus far focused on the role of cell-autonomous gene function. Yet, cortical neuron migration in situ is a complex process and migrating neurons traverse along diverse cellular compartments and environments. The role of tissue-wide properties and genetic state in radial neuron migration is however not well understood. Here, we utilized Mosaic Analysis with Double Markers (MADM) technology to either sparsely or globally delete gene function followed by quantitative single cell phenotyping. The MADM-based gene ablation paradigms in combination with computational modeling demonstrated that global tissue-wide effects predominate cell-autonomous gene function albeit in a gene-specific manner. Our results thus suggest that the genetic landscape in a tissue critically impacts the overall migration phenotype of individual cortical projection neurons. In a broader context our findings imply that global tissue-wide effects represent an essential component of the underlying etiology associated with focal malformations of cortical development (FMCD) in particular, and neurological diseases in general.
We thank A. Sommer and C. Czepe (VBCF GmbH, NGS Unit), L. Andersen, J. Sonntag, and J. Renno for technical support and/or initial experiments; M. Sixt, J. Nimpf and all members of the Hippenmeyer lab for discussion. This research was supported by the Scientific Service Units (SSU) of IST Austria through resources provided by the Imaging & Optics Facility (IOF), Lab Support Facility (LSF), and Preclinical Facility (PCF). A.H.H. was a recipient of a DOC Fellowship (24812) of the Austrian Academy of Sciences. This work also received support from IST Austria institutional funds; the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007-2013) under REA grant agreement No 618444 to S.H.
Hansen AH, Pauler F, Riedl M, et al. Tissue-wide effects overrule cell-intrinsic gene function in cortical projection neuron migration. bioRxiv. doi:10.1101/2022.02.16.480659
Hansen, A. H., Pauler, F., Riedl, M., Streicher, C., Heger, A.-M., Laukoter, S., … Hippenmeyer, S. (n.d.). Tissue-wide effects overrule cell-intrinsic gene function in cortical projection neuron migration. bioRxiv. Cold Spring Harbor Laboratory. https://doi.org/10.1101/2022.02.16.480659
Hansen, Andi H, Florian Pauler, Michael Riedl, Carmen Streicher, Anna-Magdalena Heger, Susanne Laukoter, Christoph M Sommer, et al. “Tissue-Wide Effects Overrule Cell-Intrinsic Gene Function in Cortical Projection Neuron Migration.” BioRxiv. Cold Spring Harbor Laboratory, n.d. https://doi.org/10.1101/2022.02.16.480659.
A. H. Hansen et al., “Tissue-wide effects overrule cell-intrinsic gene function in cortical projection neuron migration,” bioRxiv. Cold Spring Harbor Laboratory.
Hansen AH, Pauler F, Riedl M, Streicher C, Heger A-M, Laukoter S, Sommer CM, Nicolas A, Hof B, Tsai LH, Rülicke T, Hippenmeyer S. Tissue-wide effects overrule cell-intrinsic gene function in cortical projection neuron migration. bioRxiv, 10.1101/2022.02.16.480659.
Hansen, Andi H., et al. “Tissue-Wide Effects Overrule Cell-Intrinsic Gene Function in Cortical Projection Neuron Migration.” BioRxiv, Cold Spring Harbor Laboratory, doi:10.1101/2022.02.16.480659.