Thalamocortical axons control the cytoarchitecture of neocortical layers by area-specific supply of VGF

  1. Haruka Sato  Is a corresponding author
  2. Jun Hatakeyama
  3. Takuji Iwasato
  4. Kimi Araki
  5. Nobuhiko Yamamoto
  6. Kenji Shimamura  Is a corresponding author
  1. Kumamoto University, Japan
  2. National Institute of Genetics, Japan
  3. Osaka University, Japan

Abstract

Neuronal abundance and thickness of each cortical layer is specific to each area, but how this fundamental feature arises during development remains poorly understood. While some of area-specific features are controlled by intrinsic cues such as morphogens and transcription factors, the exact influence and mechanisms of action by cues extrinsic to the cortex, in particular the thalamic axons, have not been fully established. Here we identify a thalamus-derived factor, VGF, which is indispensable for thalamocortical axons to maintain the proper amount of layer 4 neurons in the mouse sensory cortices. This process is prerequisite for further maturation of the primary somatosensory area, such as barrel field formation instructed by a neuronal activity-dependent mechanism. Our results provide an actual case in which highly site-specific axon projection confers further regional complexity upon the target field through locally secreting signaling molecules from axon terminals.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files; Source data files have been provided for Figures 1-7 and Figure 1-figure supplement 1, Figure 2-figure supplement 1, 2, Figure 5-figure supplment 2, Figure 7-figure supplement 1, 2.

Article and author information

Author details

  1. Haruka Sato

    Department of Brain Morphogenesis, Kumamoto University, Kumamoto, Japan
    For correspondence
    stharuka@kumamoto-u.ac.jp
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6839-0146
  2. Jun Hatakeyama

    Department of Brain Morphogenesis, Kumamoto University, Kumamoto, Japan
    Competing interests
    The authors declare that no competing interests exist.
  3. Takuji Iwasato

    Laboratory of Mammalian Neural Circuits, National Institute of Genetics, Mishima, Japan
    Competing interests
    The authors declare that no competing interests exist.
  4. Kimi Araki

    Department of Brain Morphogenesis, Kumamoto University, Kumamoto, Japan
    Competing interests
    The authors declare that no competing interests exist.
  5. Nobuhiko Yamamoto

    Laboratory of Cellular and Molecular Neurobiology, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan
    Competing interests
    The authors declare that no competing interests exist.
  6. Kenji Shimamura

    Department of Brain Morphogenesis, Kumamoto University, Kumamoto, Japan
    For correspondence
    simamura@kumamoto-u.ac.jp
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7102-6513

Funding

Japan Society for the Promotion of Science (KM101-2587054400)

  • Haruka Sato

Ministry of Education, Culture, Sports, Science and Technology (JP16H06276)

  • Kimi Araki

Ministry of Education, Culture, Sports, Science and Technology (18GS0329-01)

  • Kenji Shimamura

Ministry of Education, Culture, Sports, Science and Technology (JP16K07375)

  • Kenji Shimamura

Japan Society for the Promotion of Science (KM100-2633200)

  • Haruka Sato

Japan Society for the Promotion of Science (KM101-18K1483900)

  • Haruka Sato

Ministry of Education, Culture, Sports, Science and Technology (JP06J08049)

  • Jun Hatakeyama

Ministry of Education, Culture, Sports, Science and Technology (JP21870030)

  • Jun Hatakeyama

Ministry of Education, Culture, Sports, Science and Technology (JP24790288)

  • Jun Hatakeyama

Ministry of Education, Culture, Sports, Science and Technology (JP15K19011)

  • Jun Hatakeyama

Ministry of Education, Culture, Sports, Science and Technology (JP16H01449)

  • Jun Hatakeyama

Ministry of Education, Culture, Sports, Science and Technology (JP17H05771)

  • Jun Hatakeyama

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 guidelines for laboratory animals of Kumamoto University and the Japan Neuroscience Society. All of the animals were handled according to approved institutional animal care and protocols by the Committee on the Ethics of Animal Experiments of Kumamoto University (Permit Number: 27-124, A29-080, 2019-110, 2020-055). All surgery was performed under sodium pentobarbital anesthesia, and every effort was made to minimize suffering.

Reviewing Editor

  1. Carol A Mason, Columbia University, United States

Publication history

  1. Preprint posted: February 14, 2021 (view preprint)
  2. Received: February 15, 2021
  3. Accepted: March 12, 2022
  4. Accepted Manuscript published: March 15, 2022 (version 1)
  5. Version of Record published: March 28, 2022 (version 2)

Copyright

© 2022, Sato 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

  • 1,020
    Page views
  • 220
    Downloads
  • 2
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

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. Haruka Sato
  2. Jun Hatakeyama
  3. Takuji Iwasato
  4. Kimi Araki
  5. Nobuhiko Yamamoto
  6. Kenji Shimamura
(2022)
Thalamocortical axons control the cytoarchitecture of neocortical layers by area-specific supply of VGF
eLife 11:e67549.
https://doi.org/10.7554/eLife.67549

Further reading

    1. Developmental Biology
    2. Neuroscience
    Emily L Heckman, Chris Q Doe
    Research Advance Updated

    The organization of neural circuits determines nervous system function. Variability can arise during neural circuit development (e.g. neurite morphology, axon/dendrite position). To ensure robust nervous system function, mechanisms must exist to accommodate variation in neurite positioning during circuit formation. Previously, we developed a model system in the Drosophila ventral nerve cord to conditionally induce positional variability of a proprioceptive sensory axon terminal, and used this model to show that when we altered the presynaptic position of the sensory neuron, its major postsynaptic interneuron partner modified its dendritic arbor to match the presynaptic contact, resulting in functional synaptic input (Sales et al., 2019). Here, we investigate the cellular mechanisms by which the interneuron dendrites detect and match variation in presynaptic partner location and input strength. We manipulate the presynaptic sensory neuron by (a) ablation; (b) silencing or activation; or (c) altering its location in the neuropil. From these experiments we conclude that there are two opposing mechanisms used to establish functional connectivity in the face of presynaptic variability: presynaptic contact stimulates dendrite outgrowth locally, whereas presynaptic activity inhibits postsynaptic dendrite outgrowth globally. These mechanisms are only active during an early larval critical period for structural plasticity. Collectively, our data provide new insights into dendrite development, identifying mechanisms that allow dendrites to flexibly respond to developmental variability in presynaptic location and input strength.

    1. Developmental Biology
    Hidenobu Miyazawa, Marteinn T Snaebjornsson ... Alexander Aulehla
    Research Article

    How cellular metabolic state impacts cellular programs is a fundamental, unresolved question. Here we investigated how glycolytic flux impacts embryonic development, using presomitic mesoderm (PSM) patterning as the experimental model. First, we identified fructose 1,6-bisphosphate (FBP) as an in vivo sentinel metabolite that mirrors glycolytic flux within PSM cells of post-implantation mouse embryos. We found that medium-supplementation with FBP, but not with other glycolytic metabolites, such as fructose 6-phosphate and 3-phosphoglycerate, impaired mesoderm segmentation. To genetically manipulate glycolytic flux and FBP levels, we generated a mouse model enabling the conditional overexpression of dominant active, cytoplasmic PFKFB3 (cytoPFKFB3). Overexpression of cytoPFKFB3 indeed led to increased glycolytic flux/FBP levels and caused an impairment of mesoderm segmentation, paralleled by the downregulation of Wnt-signaling, reminiscent of the effects seen upon FBP-supplementation. To probe for mechanisms underlying glycolytic flux-signaling, we performed subcellular proteome analysis and revealed that cytoPFKFB3 overexpression altered subcellular localization of certain proteins, including glycolytic enzymes, in PSM cells. Specifically, we revealed that FBP supplementation caused depletion of Pfkl and Aldoa from the nuclear-soluble fraction. Combined, we propose that FBP functions as a flux-signaling metabolite connecting glycolysis and PSM patterning, potentially through modulating subcellular protein localization.