FGF8-mediated gene regulation affects regional identity in human cerebral organoids

  1. Michele Bertacchi  Is a corresponding author
  2. Gwendoline Maharaux
  3. Agnès Loubat
  4. Matthieu Jung
  5. Michèle Studer  Is a corresponding author
  1. University Côte d'Azur, France
  2. Université Cote d'Azur, France
  3. Institut de Génétique et de Biologie Moléculaire et Cellulaire, France

Abstract

The morphogen FGF8 establishes graded positional cues imparting regional cellular responses via modulation of early target genes. The roles of FGF signaling and its effector genes remain poorly characterized in human experimental models mimicking early fetal telencephalic development. We used hiPSC-derived cerebral organoids as an in vitro platform to investigate the effect of FGF8 signaling on neural identity and differentiation. We found that FGF8 treatment increases cellular heterogeneity, leading to distinct telencephalic and mesencephalic-like domains that co-develop in multi-regional organoids. Within telencephalic domains, FGF8 affects the anteroposterior and dorsoventral identity of neural progenitors and the balance between GABAergic and glutamatergic neurons, thus impacting spontaneous neuronal network activity. Moreover, FGF8 efficiently modulates key regulators responsible for several human neurodevelopmental disorders. Overall, our results show that FGF8 signaling is directly involved in both regional patterning and cellular diversity in human cerebral organoids and in modulating genes associated with normal and pathological neural development.

Data availability

The raw data from the single-cell RNA sequencing (scRNA-seq) experiments have been deposited in the NCBI Gene Expression Omnibus (GEO) and are publicly available under the accession number GSE276558. Further details can be accessed at the linked repository. Additional data for the graphs of immunostaining pixel intensity, cell counting, or real-time RT-PCR are provided as Source data linked to the images.

The following data sets were generated

Article and author information

Author details

  1. Michele Bertacchi

    Institute of Biology Valrose, University Côte d'Azur, Nice, France
    For correspondence
    Michele.BERTACCHI@univ-cotedazur.fr
    Competing interests
    The authors declare that no competing interests exist.
  2. Gwendoline Maharaux

    Institute of Biology Valrose, University Côte d'Azur, Nice, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Agnès Loubat

    Institute of Biology Valrose, Université Cote d'Azur, Nice, France
    Competing interests
    The authors declare that no competing interests exist.
  4. Matthieu Jung

    GenomEast platform, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France
    Competing interests
    The authors declare that no competing interests exist.
  5. Michèle Studer

    Institute of Biology Valrose, University Côte d'Azur, Nice, France
    For correspondence
    michele.studer@unice.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7105-2957

Funding

Agence Nationale de la Recherche (IDEX UCAJedi ANR-15-IDEX-01)

  • Michèle Studer

Fondation pour la Recherche Médicale (EQU202003010222)

  • Michèle Studer

Fondation de France (00123416)

  • Michèle Studer

Agence Nationale de la Recherche (ANR-21-NEU2-0003-03)

  • Michèle Studer

Agence Nationale de la Recherche (ANR-10-INBS-0009)

  • Matthieu Jung

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

Copyright

© 2024, Bertacchi et al.

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 111
    views
  • 37
    downloads
  • 0
    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. Michele Bertacchi
  2. Gwendoline Maharaux
  3. Agnès Loubat
  4. Matthieu Jung
  5. Michèle Studer
(2024)
FGF8-mediated gene regulation affects regional identity in human cerebral organoids
eLife 13:e98096.
https://doi.org/10.7554/eLife.98096

Share this article

https://doi.org/10.7554/eLife.98096

Further reading

    1. Developmental Biology
    Shuhei So, Masayo Asakawa, Hitoshi Sawa
    Research Article

    Organogenesis requires the proper production of diverse cell types and their positioning/migration. However, the coordination of these processes during development remains poorly understood. The gonad in C. elegans exhibits a mirror-symmetric structure guided by the migration of distal tip cells (DTCs), which result from asymmetric divisions of somatic gonadal precursors (SGPs; Z1 and Z4). We found that the polarity of Z1 and Z4, which possess mirror-symmetric orientation, is controlled by the redundant functions of the LIN-17/Frizzled receptor and three Wnt proteins (CWN-1, CWN-2, and EGL-20) with distinct functions. In lin-17 mutants, CWN-2 promotes normal polarity in both Z1 and Z4, while CWN-1 promotes reverse and normal polarity in Z1 and Z4, respectively. In contrast, EGL-20 inhibits the polarization of both Z1 and Z4. In lin-17 egl-20 cwn-2 triple mutants with a polarity reversal of Z1, DTCs from Z1 frequently miss-migrate to the posterior side. Our further analysis demonstrates that the mis-positioning of DTCs in the gonad due to the polarity reversal of Z1 leads to mis-migration. Similar mis-migration was also observed in cki-1(RNAi) animals producing ectopic DTCs. These results highlight the role of Wnt signaling in coordinating the production and migration of DTCs to establish a mirror-symmetric organ.

    1. Cell Biology
    2. Developmental Biology
    Sarah Rubin, Ankit Agrawal ... Elazar Zelzer
    Research Article Updated

    Chondrocyte columns, which are a hallmark of growth plate architecture, play a central role in bone elongation. Columns are formed by clonal expansion following rotation of the division plane, resulting in a stack of cells oriented parallel to the growth direction. In this work, we analyzed hundreds of Confetti multicolor clones in growth plates of mouse embryos using a pipeline comprising 3D imaging and algorithms for morphometric analysis. Surprisingly, analysis of the elevation angles between neighboring pairs of cells revealed that most cells did not display the typical stacking pattern associated with column formation, implying incomplete rotation of the division plane. Morphological analysis revealed that although embryonic clones were elongated, they formed clusters oriented perpendicular to the growth direction. Analysis of growth plates of postnatal mice revealed both complex columns, composed of ordered and disordered cell stacks, and small, disorganized clusters located in the outer edges. Finally, correlation between the temporal dynamics of the ratios between clusters and columns and between bone elongation and expansion suggests that clusters may promote expansion, whereas columns support elongation. Overall, our findings support the idea that modulations of division plane rotation of proliferating chondrocytes determines the formation of either clusters or columns, a multifunctional design that regulates morphogenesis throughout pre- and postnatal bone growth. Broadly, this work provides a new understanding of the cellular mechanisms underlying growth plate activity and bone elongation during development.