1. Developmental Biology
  2. Stem Cells and Regenerative Medicine

Imprinted Dlk1 dosage as a size determinant of the mammalian pituitary gland

  1. Valeria Scagliotti
  2. Maria Lillina Vignola
  3. Thea L Willis
  4. Mark Howard
  5. Eugenia Marinelli
  6. Carles Gaston-Massuet
  7. Cynthia Lilian Andoniadou
  8. Marika Charalambous  Is a corresponding author
  1. King's College London, United Kingdom
  2. Queen Mary University of London, United Kingdom
https://doi.org/10.7554/eLife.84092
Share this article
Cite this article
  1. Valeria Scagliotti
  2. Maria Lillina Vignola
  3. Thea L Willis
  4. Mark Howard
  5. Eugenia Marinelli
  6. Carles Gaston-Massuet
  7. Cynthia Lilian Andoniadou
  8. Marika Charalambous
(2023)
Imprinted Dlk1 dosage as a size determinant of the mammalian pituitary gland
eLife 12:e84092.
https://doi.org/10.7554/eLife.84092
  2. Download BibTeX
  3. Download .RIS

Abstract

Co-regulated genes of the Imprinted Gene Network are involved in the control of growth and body size, and imprinted gene dysfunction underlies human paediatric disorders involving the endocrine system. Imprinted genes are highly expressed in the pituitary gland, among them, Dlk1, a paternally expressed gene whose membrane-bound and secreted protein products can regulate proliferation and differentiation of multiple stem cell populations. Dosage of circulating DLK1 has been previously implicated in the control of growth through unknown molecular mechanisms. Here we generate a series of mouse genetic models to modify levels of Dlk1 expression in the pituitary gland and demonstrate that the dosage of DLK1 modulates the process of stem cell commitment with lifelong impact on pituitary gland size. We establish that stem cells are a critical source of DLK1, where embryonic disruption alters proliferation in the anterior pituitary, leading to long-lasting consequences on growth hormone secretion later in life.

Data availability

Sequencing data have previously been deposited in GEO under accession codes GSE120410, GSE142074, GSE178454.Figure 1 - Source Data 1, Figure 4 - Source Data 1, Figure 5&6 - Source Data 1 contain the numerical data used to generate the figures.

The following previously published data sets were used

Article and author information

Author details

  1. Valeria Scagliotti

    Department of Medical and Molecular Genetics, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  2. Maria Lillina Vignola

    Department of Medical and Molecular Genetics, 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:" 0000-0001-7121-7715

  3. Thea L Willis

    Department of Medical and Molecular Genetics, 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:" 0000-0002-1794-7490

  4. Mark Howard

    Peter Gorer Department of Immunobiology, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  5. Eugenia Marinelli

    Department of Medical and Molecular Genetics, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  6. Carles Gaston-Massuet

    Centre for Endocrinology, Queen Mary University of London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  7. Cynthia Lilian Andoniadou

    Centre for Craniofacial and Regenerative Biology, 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:" 0000-0003-4311-5855

  8. Marika Charalambous

    Department of Medical and Molecular Genetics, King's College London, London, United Kingdom
    For correspondence
    marika.charalambous@kcl.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1684-5783

Funding

Medical Research Council (MR/L002345/1)

  • Mark Howard
  • Marika Charalambous

Barts Charity (MGU0551)

  • Carles Gaston-Massuet

Medical Research Council (MR/R022836/1)

  • Valeria Scagliotti
  • Eugenia Marinelli
  • Marika Charalambous

Medical Research Council (MR/T012153/1)

  • Cynthia Lilian Andoniadou

Merck Healthcare KGaA (GGI 2020)

  • Valeria Scagliotti
  • Maria Lillina Vignola
  • Marika Charalambous

Society for Endocrinology (ECR Grant)

  • Mark Howard

Guy's and St Thomas' NHS Foundation Trust (BRC-NIHR PhD studentship)

  • Maria Lillina Vignola

King's College London (Cell Therapies and Regenerative Medicine" Four-Year Welcome Trust PhD Training Program")

  • Thea L Willis

Action Medical Research (GN2272)

  • Carles Gaston-Massuet

Barts Charity (GN 417/2238)

  • Carles Gaston-Massuet

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

Copyright

© 2023, Scagliotti 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

  • 720
    views
  • 106
    downloads
  • 2
    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. Valeria Scagliotti
  2. Maria Lillina Vignola
  3. Thea L Willis
  4. Mark Howard
  5. Eugenia Marinelli
  6. Carles Gaston-Massuet
  7. Cynthia Lilian Andoniadou
  8. Marika Charalambous
(2023)
Imprinted Dlk1 dosage as a size determinant of the mammalian pituitary gland
eLife 12:e84092.
https://doi.org/10.7554/eLife.84092

Share this article

https://doi.org/10.7554/eLife.84092

Categories and tags

Research organism

Further reading

    1. Developmental Biology

    Opposing roles for Bmp signalling during the development of electrosensory lateral line organs

    Alexander S Campbell, Martin Minařík ... Clare VH Baker
    Research Article Updated

    The lateral line system enables fishes and aquatic-stage amphibians to detect local water movement via mechanosensory hair cells in neuromasts, and many species to detect weak electric fields via electroreceptors (modified hair cells) in ampullary organs. Both neuromasts and ampullary organs develop from lateral line placodes, but the molecular mechanisms underpinning ampullary organ formation are understudied relative to neuromasts. This is because the ancestral lineages of zebrafish (teleosts) and Xenopus (frogs) independently lost electroreception. We identified Bmp5 as a promising candidate via differential RNA-seq in an electroreceptive ray-finned fish, the Mississippi paddlefish (Polyodon spathula; Modrell et al., 2017, eLife 6: e24197). In an experimentally tractable relative, the sterlet sturgeon (Acipenser ruthenus), we found that Bmp5 and four other Bmp pathway genes are expressed in the developing lateral line, and that Bmp signalling is active. Furthermore, CRISPR/Cas9-mediated mutagenesis targeting Bmp5 in G0-injected sterlet embryos resulted in fewer ampullary organs. Conversely, when Bmp signalling was inhibited by DMH1 treatment shortly before the formation of ampullary organ primordia, supernumerary ampullary organs developed. These data suggest that Bmp5 promotes ampullary organ development, whereas Bmp signalling via another ligand(s) prevents their overproduction. Taken together, this demonstrates opposing roles for Bmp signalling during ampullary organ formation.

    1. Developmental Biology
    2. Stem Cells and Regenerative Medicine

    Single-cell RNA sequencing of the holothurian regenerating intestine reveals the pluripotency of the coelomic epithelium

    Joshua G Medina-Feliciano, Griselle Valentín-Tirado ... José E Garcia-Arraras
    Research Article

    In holothurians, the regenerative process following evisceration involves the development of a ‘rudiment’ or ‘anlage’ at the injured end of the mesentery. This regenerating anlage plays a pivotal role in the formation of a new intestine. Despite its significance, our understanding of the molecular characteristics inherent to the constituent cells of this structure has remained limited. To address this gap, we employed state-of-the-art scRNA-seq and hybridization chain reaction fluorescent in situ hybridization analyses to discern the distinct cellular populations associated with the regeneration anlage. Through this approach, we successfully identified 13 distinct cell clusters. Among these, two clusters exhibit characteristics consistent with putative mesenchymal cells, while another four show features akin to coelomocyte cell populations. The remaining seven cell clusters collectively form a large group encompassing the coelomic epithelium of the regenerating anlage and mesentery. Within this large group of clusters, we recognized previously documented cell populations such as muscle precursors, neuroepithelial cells, and actively proliferating cells. Strikingly, our analysis provides data for identifying at least four other cellular populations that we define as the precursor cells of the growing anlage. Consequently, our findings strengthen the hypothesis that the coelomic epithelium of the anlage is a pluripotent tissue that gives rise to diverse cell types of the regenerating intestinal organ. Moreover, our results provide the initial view into the transcriptomic analysis of cell populations responsible for the amazing regenerative capabilities of echinoderms.

    1. Cell Biology
    2. Developmental Biology

    Rediscovering the rete ovarii, a secreting auxiliary structure to the ovary

    Dilara N Anbarci, Jennifer McKey ... Blanche Capel
    Research Article

    The rete ovarii (RO) is an appendage of the ovary that has been given little attention. Although the RO appears in drawings of the ovary in early versions of Gray’s Anatomy, it disappeared from recent textbooks, and is often dismissed as a functionless vestige in the adult ovary. Using PAX8 immunostaining and confocal microscopy, we characterized the fetal development of the RO in the context of the mouse ovary. The RO consists of three distinct regions that persist in adult life, the intraovarian rete (IOR), the extraovarian rete (EOR), and the connecting rete (CR). While the cells of the IOR appear to form solid cords within the ovary, the EOR rapidly develops into a convoluted tubular epithelium ending in a distal dilated tip. Cells of the EOR are ciliated and exhibit cellular trafficking capabilities. The CR, connecting the EOR to the IOR, gradually acquires tubular epithelial characteristics by birth. Using microinjections into the distal dilated tip of the EOR, we found that luminal contents flow toward the ovary. Mass spectrometry revealed that the EOR lumen contains secreted proteins potentially important for ovarian function. We show that the cells of the EOR are closely associated with vasculature and macrophages, and are contacted by neuronal projections, consistent with a role as a sensory appendage of the ovary. The direct proximity of the RO to the ovary and its integration with the extraovarian landscape suggest that it plays an important role in ovary development and homeostasis.