Cell type composition and circuit organization of clonally related excitatory neurons in the juvenile mouse neocortex
- University of California, San Francisco, United States
- Baylor College of Medicine, United States
- University of Tübingen, Germany
- Karolinska Institutet, Sweden
Abstract
Clones of excitatory neurons derived from a common progenitor have been proposed to serve as elementary information processing modules in the neocortex. To characterize the cell types and circuit diagram of clonally related neurons, we performed multi-cell patch clamp recordings and Patch-seq on neurons derived from Nestin-positive progenitors labeled by tamoxifen induction at embryonic day 10.5. The resulting clones are derived from two radial glia on average, span cortical layers 2-6, and are composed of a random sampling of transcriptomic cell types. We find an interaction between shared lineage and connectivity: related neurons are more likely to be connected vertically across cortical layers, but not laterally within the same layer. These findings challenge the view that related neurons show uniformly increased connectivity and suggest that integration of vertical intra-clonal input with lateral inter-clonal input may represent a developmentally programmed connectivity motif supporting the emergence of functional circuits.
Data availability
Sequencing data have been deposited in GEO under accession code GSE140946. All data generated or analyzed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1, 2, 3 and 4. The source data provided for Figure 4 also apply to Figure 5 and Table 1.
-
Cell type composition and circuit organization of neocortical radial clonesNCBI Gene Expression Omnibus, GSE140946.
Article and author information
Author details
Kimberley F Tolias
Andreas Savas Tolias
Funding
Baylor College of Medicine (Optical Imaging and Vital Microscopy Core)
- Andreas Savas Tolias
Baylor College of Medicine (Faculty start-up fund)
- Xialong Jiang
National Institutes of Health (F30MH095440,T32GM007330)
- Cathryn R Cadwell
National Institutes of Health (F30MH112312)
- Paul G Fahey
Baylor Research Advocates for Student Scientists (BRASS Scholar Award)
- Cathryn R Cadwell
- Paul G Fahey
National Institutes of Health (R01MH103108,R01DA028525,DP1EY023176,P30EY002520,T32EY07001,DP1OD008301)
- Andreas Savas Tolias
National Science Foundation (707359)
- Andreas Savas Tolias
Svenska Forskningsrådet Formas
- Rickard Sandberg
Vallee Foundation
- Rickard Sandberg
Deutsche Forschungsgemeinschaft (EXC 2064,BE5601/4-1)
- Philipp Berens
Bundesministerium für Bildung und Forschung (FKZ 01GQ1601)
- Philipp Berens
McKnight Foundation (McKnight Scholar Award)
- Andreas Savas Tolias
Arnold and Mabel Beckman Foundation (Young Investigator Award)
- Andreas Savas Tolias
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to an approved institutional animal care and use committee (IACUC) protocol of Baylor College of Medicine (protocol # AN-4703). Every effort was made to minimize suffering.
Copyright
© 2020, Cadwell 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
-
- 4,215
- views
-
- 641
- downloads
-
- 44
- 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)
Cell type composition and circuit organization of clonally related excitatory neurons in the juvenile mouse neocortex
eLife 9:e52951.
https://doi.org/10.7554/eLife.52951
Further reading
-
- Developmental Biology
Apical constriction is a basic mechanism for epithelial morphogenesis, making columnar cells into wedge shape and bending a flat cell sheet. It has long been thought that an apically localized myosin generates a contractile force and drives the cell deformation. However, when we tested the increased apical surface contractility in a cellular Potts model simulation, the constriction increased pressure inside the cell and pushed its lateral surface outward, making the cells adopt a drop shape instead of the expected wedge shape. To keep the lateral surface straight, we considered an alternative model in which the cell shape was determined by cell membrane elasticity and endocytosis, and the increased pressure is balanced among the cells. The cellular Potts model simulation succeeded in reproducing the apical constriction, and it also suggested that a too strong apical surface tension might prevent the tissue invagination.
-
- Cancer Biology
- Developmental Biology
Missense ‘hotspot’ mutations localized in six p53 codons account for 20% of TP53 mutations in human cancers. Hotspot p53 mutants have lost the tumor suppressive functions of the wildtype protein, but whether and how they may gain additional functions promoting tumorigenesis remain controversial. Here, we generated Trp53Y217C, a mouse model of the human hotspot mutant TP53Y220C. DNA damage responses were lost in Trp53Y217C/Y217C (Trp53YC/YC) cells, and Trp53YC/YC fibroblasts exhibited increased chromosome instability compared to Trp53-/- cells. Furthermore, Trp53YC/YC male mice died earlier than Trp53-/- males, with more aggressive thymic lymphomas. This correlated with an increased expression of inflammation-related genes in Trp53YC/YC thymic cells compared to Trp53-/- cells. Surprisingly, we recovered only one Trp53YC/YC female for 22 Trp53YC/YC males at weaning, a skewed distribution explained by a high frequency of Trp53YC/YC female embryos with exencephaly and the death of most Trp53YC/YC female neonates. Strikingly, however, when we treated pregnant females with the anti-inflammatory drug supformin (LCC-12), we observed a fivefold increase in the proportion of viable Trp53YC/YC weaned females in their progeny. Together, these data suggest that the p53Y217C mutation not only abrogates wildtype p53 functions but also promotes inflammation, with oncogenic effects in males and teratogenic effects in females.
