Abstract

The development of connectivity between the thalamus and maturing cortex is a fundamental process in the second half of human gestation, establishing the neural circuits that are the basis for several important brain functions. In this study, we acquired high-resolution in utero diffusion MRI from 140 fetuses as part of the Developing Human Connectome Project, to examine the emergence of thalamocortical white matter over the second to third trimester. We delineate developing thalamocortical pathways and parcellate the fetal thalamus according to its cortical connectivity using diffusion tractography. We then quantify microstructural tissue components along the tracts in fetal compartments that are critical substrates for white matter maturation, such as the subplate and intermediate zone. We identify patterns of change in the diffusion metrics that reflect critical neurobiological transitions occurring in the second to third trimester, such as the disassembly of radial glial scaffolding and the lamination of the cortical plate. These maturational trajectories of MR signal in transient fetal compartments provide a normative reference to complement histological knowledge, facilitating future studies to establish how developmental disruptions in these regions contribute to pathophysiology.

Data availability

Developing Human Connectome project data is open-access and available for download following completion of a data-usage agreement via: http://www.developingconnectome.org/. Data will also be available at: https://nda.nih.gov/edit_collection.html?id=3955

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Sian Wilson

    Centre for the Developing Brain, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4617-3583
  2. Maximilian Pietsch

    Centre for the Developing Brain, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Lucilio Cordero-Grande

    Centre for the Developing Brain, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Daan Christiaens

    Centre for the Developing Brain, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Alena Uus

    Department of Biomedical Engineering, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Vyacheslav R Karolis

    Centre for the Developing Brain, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Vanessa Kyriakopoulou

    Centre for the Developing Brain, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Kathleen Colford

    Centre for the Developing Brain, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Anthony N Price

    Centre for the Developing Brain, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Jana Hutter

    Centre for the Developing Brain, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Mary A Rutherford

    Centre for the Developing Brain, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. Emer J Hughes

    Centre for the Developing Brain, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  13. Serena J Counsell

    Centre for the Developing Brain, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8033-5673
  14. Jacques-Donald Tournier

    Centre for the Developing Brain, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  15. Joseph V Hajnal

    Centre for the Developing Brain, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  16. A David Edwards

    Department of Biomedical Engineering, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4801-7066
  17. Jonathan O'Muicheartaigh

    Centre for the Developing Brain, King's College London, London, United Kingdom
    For correspondence
    jonathanom@kcl.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
  18. Tomoki Arichi

    Centre for the Developing Brain, King's College London, London, United Kingdom
    For correspondence
    tomoki.arichi@kcl.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3550-1644

Funding

European Research Council (Seventh Framework Programme: FP/2007/2013)

  • Maximilian Pietsch
  • Lucilio Cordero-Grande
  • Daan Christiaens
  • Vyacheslav R Karolis
  • Vanessa Kyriakopoulou
  • Anthony N Price
  • Jana Hutter
  • Emer J Hughes
  • Jacques-Donald Tournier
  • Joseph V Hajnal
  • A David Edwards

Wellcome Trust (Sir Henry Dale Fellowship: 206675/Z/17/Z)

  • Jonathan O'Muicheartaigh

Medical Research Council Centre for Neurodevelopmental Disorders (MR/N0266063/1)

  • Sian Wilson
  • Mary A Rutherford
  • A David Edwards
  • Jonathan O'Muicheartaigh
  • Tomoki Arichi

Medical Research Council (Translation support fellowship: MR/V036874/1)

  • Vyacheslav R Karolis
  • Tomoki Arichi

Wellcome / EPSRC Centre for Biomedical Engineering, Kings College London (WT 203148/Z/16/Z)

  • Anthony N Price
  • Jana Hutter
  • Jacques-Donald Tournier
  • Joseph V Hajnal

Medical Research Council (Clinician Scientist Fellowship MR/P008712/1)

  • Tomoki Arichi

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

Ethics

Human subjects: The study was approved by the UK Health Research Authority (Research Ethics Committee reference number: 14/LO/1169) and written parental consent was obtained in every case for imaging and open data release of the anonymized data.

Copyright

© 2023, Wilson 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

  • 1,244
    views
  • 225
    downloads
  • 19
    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. Sian Wilson
  2. Maximilian Pietsch
  3. Lucilio Cordero-Grande
  4. Daan Christiaens
  5. Alena Uus
  6. Vyacheslav R Karolis
  7. Vanessa Kyriakopoulou
  8. Kathleen Colford
  9. Anthony N Price
  10. Jana Hutter
  11. Mary A Rutherford
  12. Emer J Hughes
  13. Serena J Counsell
  14. Jacques-Donald Tournier
  15. Joseph V Hajnal
  16. A David Edwards
  17. Jonathan O'Muicheartaigh
  18. Tomoki Arichi
(2023)
Spatiotemporal tissue maturation of thalamocortical pathways in the human fetal brain
eLife 12:e83727.
https://doi.org/10.7554/eLife.83727

Share this article

https://doi.org/10.7554/eLife.83727

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.