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
Figures
Figure 1 with 1 supplement
Identification of pyramidal cell lineages with low-titer conditional reporter retroviruses.
(a) Experimental paradigm. (b) Schematic representation of the expected labeling outcomes in retroviral lineage tracing experiments. (c–c’) Serial 100 μm coronal sections through the telencephalon …
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Figure 1—source data 1
E9.5-E14.5 Neurod6Cre/+ retroviral lineages analyzed at P21.
- https://cdn.elifesciences.org/articles/51381/elife-51381-fig1-data1-v2.xlsx
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Figure 1—source data 2
Summary of numerical data that are represented in graphs.
- https://cdn.elifesciences.org/articles/51381/elife-51381-fig1-data2-v2.xlsx
Figure 1—figure supplement 1
Sparse labeling of neuronal clones with low-titer retroviral infection.
(a) Experimental paradigm. (b) Fraction of neuron clusters containing cells labeled with one or two reporters. (c,d) Serial 100 μm coronal sections through the telencephalon of P21 Neurod6Cre/+ mice …
Figure 2 with 1 supplement
Retroviral-based lineage tracing reveals diverse lineage outcomes.
(a) Experimental paradigm. The bottom panel illustrates the expected labeling outcome following retroviral infection of an RGC undergoing a neurogenic cell division in which the viral integration …
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Figure 2—source data 1
E12.5 Neurod6Cre/+ retroviral lineages analyzed at P21.
- https://cdn.elifesciences.org/articles/51381/elife-51381-fig2-data1-v2.xlsx
Figure 2—figure supplement 1
Lineage tracing of Tbr2+ intermediate progenitor cells.
(a) Experimental paradigm. The bottom panel illustrates the expected labeling outcome of the division of a Tbr2+ intermediate progenitor cell. (b,c) 100 μm coronal sections through the cortex of P21 …
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Figure 2—figure supplement 1—source data 1
E12.5 Tbr2CreERT2/+;RCL-Gfp lineages analyzed at P21.
- https://cdn.elifesciences.org/articles/51381/elife-51381-fig2-figsupp1-data1-v2.xlsx
Figure 3 with 1 supplement
Lineage tracing using MADM identifies a small fraction of deep layer-restricted cortical lineages.
(a) Experimental paradigm. The bottom panel illustrates the expected labeling outcome of a neurogenic RGC division following inducible MADM-based lineage tracing in which two subclones are labeled …
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Figure 3—source data 1
E12.5 Emx1-CreERT2;MADMTG/GT lineages analyzed at P21.
- https://cdn.elifesciences.org/articles/51381/elife-51381-fig3-data1-v2.xlsx
Figure 3—figure supplement 1
Large MADM subclones reveal a small fraction of artifactual superficial layer-restricted lineages in the retroviral experiments.
(a) Experimental paradigm. The bottom panel illustrates the expected labeling outcome of a neurogenic RGC division following inducible MADM-based lineage tracing in which two subclones are labeled …
Figure 4 with 1 supplement
A fraction of early-quiescent cortical progenitors generates superficial layer-restricted lineages.
(a) Experimental paradigm. The bottom panel illustrates the expected labeling outcome of a neurogenic RGC division following inducible conditional reporter lineage tracing in Emx1-CreERT2;RCL-Gfp …
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Figure 4—source data 1
E12.5 Emx1-CreERT2;RCL-Gfp lineages analyzed at P21.
- https://cdn.elifesciences.org/articles/51381/elife-51381-fig4-data1-v2.xlsx
Figure 4—figure supplement 1
Superficial layer-restricted lineages in the murine cerebral cortex.
(a–d) Serial 100 µm coronal sections through the cortex of P21 Emx1-CreERT2; RCL-Gfp mice treated with tamoxifen at E12.5. The images show examples of superficial lineages. The schemas collapse …
Figure 5 with 3 supplements
Translaminar lineages adopt very heterogeneous configurations.
(a) Experimental paradigm. The bottom panel illustrates the expected labeling outcome of a neurogenic RGC division following inducible conditional reporter lineage tracing in Emx1-CreERT2;RCL-Gfp …
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Figure 5—source data 1
Projection neuron markers in E12.5 Emx1-CreERT2;RCL-Gfp all-layer lineages analyzed at P21.
- https://cdn.elifesciences.org/articles/51381/elife-51381-fig5-data1-v2.xlsx
Figure 5—figure supplement 1
Retrovirus and MADM labeled lineages exhibit a diversity of laminar configurations.
(a) Experimental paradigm. The right panel illustrates the expected labeling outcome following retroviral infection of an RGC undergoing a neurogenic cell division in which the viral integration …
Figure 5—figure supplement 2
Identification of pyramidal cell subclasses.
(a) Experimental paradigm. The bottom panel illustrates the expected labeling outcome of a neurogenic RGC division following inducible conditional reporter lineage tracing in Emx1-CreERT2;RCL-Gfp …
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Figure 5—figure supplement 2—source data 1
Projection neuron marker colocalization.
- https://cdn.elifesciences.org/articles/51381/elife-51381-fig5-figsupp2-data1-v2.xlsx
Figure 5—figure supplement 3
Subtle impact of pyramidal neuron cell death in final configurations of cortical neuron lineages.
(a) Experimental paradigm. The bottom panel illustrates the expected labeling outcome of a neurogenic RGC division following inducible conditional reporter lineage tracing in Emx1-CreERT2;RCL-Gfp …
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Figure 5—figure supplement 3—source data 1
E12.5 Emx1-CreERT2;RCL-Gfp lineages analyzed at P2.
- https://cdn.elifesciences.org/articles/51381/elife-51381-fig5-figsupp3-data1-v2.xlsx
Figure 6 with 1 supplement
A stochastic model of cortical neurogenesis.
(a) Number of progenitor identities required to reproduce experimental lineage configurations inferred by Bayesian modeling. The y axis represents the fraction of simulations from a total of 4000 …
Figure 6—figure supplement 1
Laminar densities of pyramidal neurons do not predict lineage structure.
(a) Fraction of cells in each cortical layer (expressed as percentage of total) in experimental and permuted lineages. (b) Clonal size distribution in experimental and permuted lineages. (c) …
Figure 7 with 1 supplement
A small number of progenitor identities underlie lineage diversity.
(a) Schematic representation of a mathematical model of cortical neurogenesis in which two different progenitor identities are modeled (Model 2). Squares represent the maximum number of stochastic …
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Figure 7—source data 1
Laminar densities in Neurod6Cre/+;RCL-Fucci2 mice analyzed at P21.
- https://cdn.elifesciences.org/articles/51381/elife-51381-fig7-data1-v2.xlsx
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Figure 7—source code 1
Lineage generation simulator.
- https://cdn.elifesciences.org/articles/51381/elife-51381-fig7-code1-v2.m
Figure 7—figure supplement 1
Stochastic models considering single and multiple programs corroborate Bayesian inference.
(a) Schematic representation of a mathematical model of cortical neurogenesis in which a unique progenitor identity is modeled (Model 1). Squares represent the maximum number of stochastic decisions …
Tables
Key resources table
| Reagent type (species) or resource | Designation | Source or reference | Identifiers | Additional information |
|---|---|---|---|---|
| Genetic reagent (M. musculus) | Neurod6Cre | PMID: 17146780 | RRID: MGI:4429427 | Dr Klaus Nave (MPI-EM) |
| Genetic reagent (M. musculus) | Emx1-CreERT2 | PMID: 16388308 Jackson laboratory | Stock: 027784 RRID: IMSR_JAX:027784 | |
| Genetic reagent (M. musculus) | Tbr2CreERT2 | PMID: 23897762 | RRID:MGI:5499789 | Dr Sebastian J Arnold (University of Freiburg) |
| Genetic reagent (M. musculus) | RCL-Gfp, RCE | PMID: 19363146 Jackson laboratory | Stock: 32037 RRID: MGI:4420759 | |
| Genetic reagent (M. musculus) | MADMTG | PMID: 21092859 Jackson laboratory | Stock: 013751 RRID:IMSR_JAX:013751 | |
| Genetic reagent (M. musculus) | MADMGT | PMID: 21092859 Jackson laboratory | Stock: 013749 RRID:IMSR_JAX:013749 | |
| Genetic reagent (M. musculus) | RCL-Fucci2a | PMID: 25486356 | RRID:IMSR_HAR:6899 | Dr Richard Mort (Lancaster University) |
| Cell line (Homo sapiens) | HEK293FT | Invitrogen | Cat: R700-07 RRID: CVCL_6911 | |
| Transfected construct (M. musculus) | rv::dio-eGFP | PMID: 23933753 Addgene | ID: 87662 | |
| Transfected construct (M. musculus) | rv::dio-mCherry | PMID: 23933753 Addgene | ID: 87664 | |
| Antibody | Anti-GFP (chicken polyclonal) | Aves Lab | Cat: GFP-1020 RRID: AB_10000240 | IF(1:2000) |
| Antibody | Anti-DsRed (rabbit polyclonal) | Clonetech | Cat: 632496 RRID: AB_10013483 | IF(1:500) |
| Antibody | Anti-mCherry (goat polyclonal) | Antibodies online | Cat: ABIN1440057 RRID: AB_11208222 | IF(1:500) |
| Antibody | Anti-Ctip2 (rat monoclonal) | Abcam | Cat: AB18465 RRID: AB_2064130 | IF(1:500) |
| Antibody | Anti-Satb2 (mouse monoclonal) | Abcam | Cat: AB51502 RRID: AB_882455 | IF(1:500) |
| Antibody | Anti-Satb2 (rabbit polyclonal) | Abcam | Cat: AB34735 RRID: AB_2301417 | IF(1:1000) |
| Antibody | Anti-Tle4 (goat polyclonal) | Gift from Dr Stefano Stifani (McGill University) | IF(1:200) | |
| Antibody | Anti-chicken IgY-Alexa fluor 488 (goat polyclonal) | TermoFisher | Cat: A-11039 RRID: AB_2534096 | IF(1:400) |
| Antibody | Anti-mouse IgG-Alexa fluor 647 (goat polyclonal) | TermoFisher | Cat: A-21240 RRID: AB_2535809 | IF(1:400) |
| Antibody | Anti-mouse IgG-biotinilated (Horse polyclonal) | Vector Labs | Cat: BA2000 RRID: AB_2313581 | IF(1:400) |
| Antibody | Anti-rat IgG-Alexa fluor 555 (goat polyclonal) | TermoFisher | Cat: A-21434 RRID: AB_2535855 | IF(1:400) |
| Antibody | Anti-goat IgG-Alexa fluor 555 (donkey polyclonal) | TermoFisher | Cat: A-21432 RRID: AB_2535853 | IF(1:400) |
| Antibody | Anti-rabbit IgG-Alexa fluor 488 (donkey polyclonal) | TermoFisher | Cat: A-21432 RRID: AB_2535853 | IF(1:400) |
| Chemical compound, drug | Tamoxifen | Sigma-Aldrich | Cat: 85256 | |
| Software, algorithm | Prism 8 | GraphPad | RRID: SCR_002798 | |
| Software, algorithm | MATLAB | Mathworks | RRID: SCR_001622 | |
| Software, algorithm | RStudio | RStudio | RRID: SCR_000432 | |
| Software, algorithm | Imaris 8 | Bitplane | RRID: SCR_007370 |
