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Tissue-wide Effects Overrule Cell-intrinsic Gene Function in Cortical Projection Neuron Migration

Andi H. Hansen, Florian M. Pauler, View ORCID ProfileMichael Riedl, Carmen Streicher, Anna Heger, Susanne Laukoter, Christoph Sommer, Armel Nicolas, View ORCID ProfileBjörn Hof, Li Huei Tsai, Thomas Rülicke, View ORCID ProfileSimon Hippenmeyer
doi: https://doi.org/10.1101/2022.02.16.480659
Andi H. Hansen
1Institute of Science and Technology Austria, Am Campus 1, 3400 Klosterneuburg, Austria
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Florian M. Pauler
1Institute of Science and Technology Austria, Am Campus 1, 3400 Klosterneuburg, Austria
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Michael Riedl
1Institute of Science and Technology Austria, Am Campus 1, 3400 Klosterneuburg, Austria
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Carmen Streicher
1Institute of Science and Technology Austria, Am Campus 1, 3400 Klosterneuburg, Austria
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Anna Heger
1Institute of Science and Technology Austria, Am Campus 1, 3400 Klosterneuburg, Austria
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Susanne Laukoter
1Institute of Science and Technology Austria, Am Campus 1, 3400 Klosterneuburg, Austria
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Christoph Sommer
1Institute of Science and Technology Austria, Am Campus 1, 3400 Klosterneuburg, Austria
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Armel Nicolas
1Institute of Science and Technology Austria, Am Campus 1, 3400 Klosterneuburg, Austria
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Björn Hof
1Institute of Science and Technology Austria, Am Campus 1, 3400 Klosterneuburg, Austria
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  • ORCID record for Björn Hof
Li Huei Tsai
2Picower Institute for Learning and Memory, MIT, Cambridge, MA 02139, USA
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Thomas Rülicke
3Department of Biomedical Sciences, University of Veterinary Medicine Vienna, 1210 Vienna, Austria
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Simon Hippenmeyer
1Institute of Science and Technology Austria, Am Campus 1, 3400 Klosterneuburg, Austria
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  • ORCID record for Simon Hippenmeyer
  • For correspondence: simon.hippenmeyer@ist.ac.at
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ABSTRACT

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.

LAY SUMMARY The assembly of the mammalian brain is a complex process and depends on tightly regulated developmental and genetic programs. The coordinated process of nerve cell (neuron) migration is essential to home neurons into their correct position which is vital for normal brain development. Disturbance of the neuron migration process at any point of development leads to severe brain malformations which result in devastating disease. To date, studies have mainly focused on cell-intrinsic gene functions controlling neuronal migration. Therefore, very little is known about the possible contribution of the cellular surrounding and tissue-wide effects. The scale and nature of such global tissue-wide effects remain completely unclear. We thus established genetic platforms based on Mosaic Analysis with Double Markers (MADM) to visualize and quantify tissue-wide effects in a defined genetic context and at single cell resolution. We found a critical predominant role of the genetic landscape and state of cellular environment affecting overall neuron migration properties. In a broader context our results suggest that global tissue-wide effects are a major component of the underlying etiology of neurological diseases such as focal malformations of cortical development (FMCD).

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted February 17, 2022.
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Tissue-wide Effects Overrule Cell-intrinsic Gene Function in Cortical Projection Neuron Migration
Andi H. Hansen, Florian M. Pauler, Michael Riedl, Carmen Streicher, Anna Heger, Susanne Laukoter, Christoph Sommer, Armel Nicolas, Björn Hof, Li Huei Tsai, Thomas Rülicke, Simon Hippenmeyer
bioRxiv 2022.02.16.480659; doi: https://doi.org/10.1101/2022.02.16.480659
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Tissue-wide Effects Overrule Cell-intrinsic Gene Function in Cortical Projection Neuron Migration
Andi H. Hansen, Florian M. Pauler, Michael Riedl, Carmen Streicher, Anna Heger, Susanne Laukoter, Christoph Sommer, Armel Nicolas, Björn Hof, Li Huei Tsai, Thomas Rülicke, Simon Hippenmeyer
bioRxiv 2022.02.16.480659; doi: https://doi.org/10.1101/2022.02.16.480659

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