A stochastic framework of neurogenesis underlies the assembly of neocortical cytoarchitecture
- King's College London, United Kingdom
- Institute of Science and Technology Austria, Austria
- University of Freiburg, Germany
- University of Sussex, United Kingdom
Abstract
The cerebral cortex contains multiple areas with distinctive cytoarchitectonical patterns, but the cellular mechanisms underlying the emergence of this diversity remain unclear. Here, we have investigated the neuronal output of individual progenitor cells in the developing mouse neocortex using a combination of methods that together circumvent the biases and limitations of individual approaches. Our experimental results indicate that progenitor cells generate pyramidal cell lineages with a wide range of sizes and laminar configurations. Mathematical modelling indicates that these outcomes are compatible with a stochastic model of cortical neurogenesis in which progenitor cells undergo a series of probabilistic decisions that lead to the specification of very heterogeneous progenies. Our findings support a mechanism for cortical neurogenesis whose flexibility would make it capable to generate the diverse cytoarchitectures that characterize distinct neocortical areas.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Funding
H2020 European Research Council (ERC-2017-AdG 787355)
- Oscar Marin
H2020 European Research Council (ERC-2016-CoG 725780)
- Simon Hippenmeyer
European Molecular Biology Organization
- Fong Kuan Wong
H2020 Marie Skłodowska-Curie Actions
- Fong Kuan Wong
Austrian Science Fund (Lise-Meitner program M 2416)
- Robert Beattie
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All procedures were approved by King's College London and IST Austria, and were performed under UK Home Office project licenses, and in accordance with Austrian Federal Ministry of Science and Research license, and European regulations (EU directive 86/609, EU decree 2001- 486).
Copyright
© 2019, Llorca et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 6,007
- views
-
- 1,193
- downloads
-
- 89
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
A stochastic framework of neurogenesis underlies the assembly of neocortical cytoarchitecture
eLife 8:e51381.
https://doi.org/10.7554/eLife.51381
Further reading
-
- Developmental Biology
- Neuroscience
Mutations in Sonic Hedgehog (SHH) signaling pathway genes, for example, Suppressor of Fused (SUFU), drive granule neuron precursors (GNP) to form medulloblastomas (MBSHH). However, how different molecular lesions in the Shh pathway drive transformation is frequently unclear, and SUFU mutations in the cerebellum seem distinct. In this study, we show that fibroblast growth factor 5 (FGF5) signaling is integral for many infantile MBSHH cases and that FGF5 expression is uniquely upregulated in infantile MBSHH tumors. Similarly, mice lacking SUFU (Sufu-cKO) ectopically express Fgf5 specifically along the secondary fissure where GNPs harbor preneoplastic lesions and show that FGFR signaling is also ectopically activated in this region. Treatment with an FGFR antagonist rescues the severe GNP hyperplasia and restores cerebellar architecture. Thus, direct inhibition of FGF signaling may be a promising and novel therapeutic candidate for infantile MBSHH.
-
- Developmental Biology
- Genetics and Genomics
The establishment and growth of the arterial endothelium requires the coordinated expression of numerous genes. However, regulation of this process is not yet fully understood. Here, we combined in silico analysis with transgenic mice and zebrafish models to characterize arterial-specific enhancers associated with eight key arterial identity genes (Acvrl1/Alk1, Cxcr4, Cxcl12, Efnb2, Gja4/Cx37, Gja5/Cx40, Nrp1 and Unc5b). Next, to elucidate the regulatory pathways upstream of arterial gene transcription, we investigated the transcription factors binding each arterial enhancer compared to a similar assessment of non-arterial endothelial enhancers. These results found that binding of SOXF and ETS factors was a common occurrence at both arterial and pan-endothelial enhancers, suggesting neither are sufficient to direct arterial specificity. Conversely, FOX motifs independent of ETS motifs were over-represented at arterial enhancers. Further, MEF2 and RBPJ binding was enriched but not ubiquitous at arterial enhancers, potentially linked to specific patterns of behaviour within the arterial endothelium. Lastly, there was no shared or arterial-specific signature for WNT-associated TCF/LEF, TGFβ/BMP-associated SMAD1/5 and SMAD2/3, shear stress-associated KLF4 or venous-enriched NR2F2. This cohort of well characterized and in vivo-verified enhancers can now provide a platform for future studies into the interaction of different transcriptional and signalling pathways with arterial gene expression.
