Imprinted Dlk1 dosage as a size determinant of the mammalian pituitary gland
- King's College London, United Kingdom
- Queen Mary University of London, United Kingdom
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.
Article and author information
Author details
Maria Lillina Vignola
Cynthia Lilian Andoniadou
Marika Charalambous
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.
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Imprinted Dlk1 dosage as a size determinant of the mammalian pituitary gland
eLife 12:e84092.
https://doi.org/10.7554/eLife.84092
Further reading
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- Developmental Biology
- Stem Cells and Regenerative Medicine
The purpose of these studies is to investigate how Sphingosine-1-phosphate (S1P) signaling regulates glial phenotype, dedifferentiation of Müller glia (MG), reprogramming into proliferating MG-derived progenitor cells (MGPCs), and neuronal differentiation of the progeny of MGPCs in the chick retina. We found that S1P-related genes are highly expressed by retinal neurons and glia, and levels of expression were dynamically regulated following retinal damage. Drug treatments that activate S1P receptor 1 (S1PR1) or increase levels of S1P suppressed the formation of MGPCs. Conversely, treatments that inhibit S1PR1 or decrease levels of S1P stimulated the formation of MGPCs. Inhibition of S1P receptors or S1P synthesis significantly enhanced the neuronal differentiation of the progeny of MGPCs. We report that S1P-related gene expression in MG is modulated by microglia and inhibition of S1P receptors or S1P synthesis partially rescues the loss of MGPC formation in damaged retinas missing microglia. Finally, we show that TGFβ/Smad3 signaling in the resting retina maintains S1PR1 expression in MG. We conclude that the S1P signaling is dynamically regulated in MG and MGPCs in the chick retina, and activation of S1P signaling depends, in part, on signals produced by reactive microglia.
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- Developmental Biology
Congenital malformations can originate from numerous genetic or non-genetic factors but in most cases the causes are unknown. Genetic disruption of nicotinamide adenine dinucleotide (NAD) de novo synthesis causes multiple malformations, collectively termed Congenital NAD Deficiency Disorder (CNDD), highlighting the necessity of this pathway during embryogenesis. Previous work in mice shows that NAD deficiency perturbs embryonic development specifically when organs are forming. While the pathway is predominantly active in the liver postnatally, the site of activity prior to and during organogenesis is unknown. Here, we used a mouse model of human CNDD and assessed pathway functionality in embryonic livers and extraembryonic tissues via gene expression, enzyme activity and metabolic analyses. We found that the extra-embryonic visceral yolk sac endoderm exclusively synthesises NAD de novo during early organogenesis before the embryonic liver takes over this function. Under CNDD-inducing conditions, visceral yolk sacs had reduced NAD levels and altered NAD-related metabolic profiles, affecting embryo metabolism. Expression of requisite pathway genes is conserved in the equivalent yolk sac cell type in humans. Our findings show that visceral yolk sac-mediated NAD de novo synthesis activity is essential for mouse embryogenesis and its perturbation causes CNDD. As mouse and human yolk sacs are functionally homologous, our data improve the understanding of human congenital malformation causation.
