Sequential addition of neuronal stem cell temporal cohorts generates a feed-forward circuit in the Drosophila larval nerve cord

Abstract

How circuits self-assemble starting from neuronal stem cells is a fundamental question in developmental neurobiology. Here, we addressed how neurons from different stem cell lineages wire with each other to form a specific circuit motif. In Drosophila larvae, we combined developmental genetics (Twin spot MARCM, Multi-color Flip Out, permanent labeling) with circuit analysis (calcium imaging, connectomics, network science). For many lineages, neuronal progeny are organized into subunits called temporal cohorts. Temporal cohorts are subsets of neurons born within a tight time window that have shared circuit level function. We find sharp transitions in patterns of input connectivity at temporal cohort boundaries. In addition, we identify a feed-forward circuit that encodes the onset of vibration stimuli. This feed-forward circuit is assembled by preferential connectivity between temporal cohorts from different lineages. Connectivity does not follow the often-cited early-to-early, late-to-late model. Instead, the circuit is formed by sequential addition of temporal cohorts from different lineages, with circuit output neurons born before circuit input neurons. Further, we generate new tools for the fly community. Our data raise the possibility that sequential addition of neurons (with outputs oldest and inputs youngest) could be one fundamental strategy for assembling feed-forward circuits.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files (Supplemental Tables 1-6)Source Data files are provided for Figures 3,4,5,6,7,9,10.13.14

Article and author information

Author details

  1. Yi-wen Wang

    Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Chris C Wreden

    Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Maayan Levy

    Committee on Computational Neuroscience, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Julia L Meng

    Program in Cell and Molecular Biology, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Zarion D Marshall

    Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Jason MacLean

    Committee on Computational Neuroscience, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Ellie Heckscher

    Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, United States
    For correspondence
    heckscher@uchicago.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7618-0616

Funding

National Institute of Neurological Disorders and Stroke (NS105748)

  • Ellie Heckscher

National Eye Institute (EY022338)

  • Jason MacLean

Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32 HD044164)

  • Zarion D Marshall

National Science Foundation (DGE-1746045)

  • Julia L Meng

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2022, Wang 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

  • 1,954
    views
  • 428
    downloads
  • 4
    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)

  1. Yi-wen Wang
  2. Chris C Wreden
  3. Maayan Levy
  4. Julia L Meng
  5. Zarion D Marshall
  6. Jason MacLean
  7. Ellie Heckscher
(2022)
Sequential addition of neuronal stem cell temporal cohorts generates a feed-forward circuit in the Drosophila larval nerve cord
eLife 11:e79276.
https://doi.org/10.7554/eLife.79276

Share this article

https://doi.org/10.7554/eLife.79276

Further reading

    1. Cancer Biology
    2. Developmental Biology
    Sara Jaber, Eliana Eldawra ... Franck Toledo
    Research Article

    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.

    1. Developmental Biology
    Mengjie Li, Aiguo Tian, Jin Jiang
    Research Advance

    Stem cell self-renewal often relies on asymmetric fate determination governed by niche signals and/or cell-intrinsic factors but how these regulatory mechanisms cooperate to promote asymmetric fate decision remains poorly understood. In adult Drosophila midgut, asymmetric Notch (N) signaling inhibits intestinal stem cell (ISC) self-renewal by promoting ISC differentiation into enteroblast (EB). We have previously shown that epithelium-derived Bone Morphogenetic Protein (BMP) promotes ISC self-renewal by antagonizing N pathway activity (Tian and Jiang, 2014). Here, we show that loss of BMP signaling results in ectopic N pathway activity even when the N ligand Delta (Dl) is depleted, and that the N inhibitor Numb acts in parallel with BMP signaling to ensure a robust ISC self-renewal program. Although Numb is asymmetrically segregated in about 80% of dividing ISCs, its activity is largely dispensable for ISC fate determination under normal homeostasis. However, Numb becomes crucial for ISC self-renewal when BMP signaling is compromised. Whereas neither Mad RNA interference nor its hypomorphic mutation led to ISC loss, inactivation of Numb in these backgrounds resulted in stem cell loss due to precocious ISC-to-EB differentiation. Furthermore, we find that numb mutations resulted in stem cell loss during midgut regeneration in response to epithelial damage that causes fluctuation in BMP pathway activity, suggesting that the asymmetrical segregation of Numb into the future ISC may provide a fail-save mechanism for ISC self-renewal by offsetting BMP pathway fluctuation, which is important for ISC maintenance in regenerative guts.