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

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.

Tissue-wide Genetic and Cellular Landscape Shapes the Execution of Sequential PRC2 Functions in Neural Stem Cell Lineage Progression

“…However, certain genes only cause a significant disruption of faithful neurogenesis upon deletion at the global tissue level (Beattie et al, 2017). The predominance of tissue-wide effects causing severe cortical malformations has recently also been reported for genes involved in migration or cell polarity (Hansen et al, 2022), thus further underlining that global tissue or non-cell-autonomous systemic effects significantly shape the early steps of cortical development such as neuron production (Hansen and Hippenmeyer, 2020).…”