Biology subjects

Vignola, M. L.

Publications and source records attributed to Vignola, M. L..

6 recordsLinked to original sources

bioRxiv2026

IAP retrotransposons contribute to the transcriptional diversity of the murine placenta

Transposable elements (TEs) have made important contributions to the evolution of the placenta, and are argued to have played a role in the wide inter-species diversification of this critical developmental organ. Co-option of TEs by host genomes has led to the genesis of important placental genes, as well as trophoblast-specific gene regulatory elements. But whilst multiple TE subfamilies have been shown to act as transcriptional enhancers in early mouse trophoblast development, it remains unclear to what extent TEs regulate placental gene expression after the establishment of a functional fetal-maternal interface. Here, we characterised the TE regulatory and transcriptional landscape in mouse placenta and gauged their evolutionary dynamics through a comparative approach. We found that overall, the gene regulatory potential of TEs is greatly diminished in differentiated mouse trophoblast when compared to their stem cell counterpart. However, evolutionarily young intracisternal A particle (IAP) elements are highly expressed in the placenta and create several alternative, placenta-specific transcriptional start sites for protein-coding genes. IAP elements that are active in the placenta drive species-specific expression of associated genes and display wide genetic diversity between mouse strains. These putative co-option events are therefore evolutionarily recent and may represent a prime example of how TE activity can drive fast placental evolution.

genetics↗

bioRxiv2025

Placental insufficiency causes fetal growth restriction in mice lacking Delta-like homologue 1

Fetal growth restriction (FGR) affects between 3-7% of pregnancies, is associated with increased perinatal morbidity and mortality, and linked to failure of placental function. The placenta is the key transient organ in pregnancy that directs nutrient transfer, intermediary metabolism and the production of hormones that drive maternal metabolic adaptations essential for pregnancy and lactation. The exchange surface of the placenta is formed in early development by the interaction between trophoblast cells that enclose the maternal blood and extraembryonic mesodermal cells that comprise the fetal vasculature. Despite recent insights into trophoblast development derived from novel in-vitro approaches, the processes driving extraembryonic mesoderm development are not well explored. This is due to a dearth of studies employing unbiased approaches to interrogate extraembryonic mesoderm cell populations. Here we use genetic labelling techniques to separate molecular events occurring in the trophoblast from those in the mesodermal layers of the placenta. In combination with conditional targeting, we show that the imprinted gene Dlk1 is a key player in providing nutrients to the embryo by controlling the placental surface area available for nutrient exchange, and by modulating the production of placental hormones that promote maternal nutrient provision in pregnancy.

developmental biology↗

bioRxiv2025

Chaperone AIP Couples mTORC1 Activation and Catabolic Metabolism During Neonatal Development

To grow and divide cells must tightly coordinate anabolic programs with the availability of nutrients and growth factors. This balance is especially critical during postnatal development, when biosynthetic and energetic demands are high, and nutrient supply and neonates have to adapt to periods of fasting. These conditions place acute stress on the proteostasis network, making autophagy essential for nutrient recycling. We found that the chaperone aryl hydrocarbon receptor-interacting protein (AIP) supports both arms of this metabolic balance: promoting anabolic PI3K-AKT signaling for mTORC1 activation and enabling catabolic processes such as proteasomal degradation and autophagy. Loss of AIP causes a severe neonatal metabolic disorder, where affected infants fail to thrive postnatally. Our findings establish AIP as a central regulator of neonatal metabolic adaptation and cellular homeostasis. One Sentence SummaryAIP integrates nutrient sensing and protein recycling to sustain neonatal survival.

developmental biology↗

bioRxiv2024

Biallelic Loss of Molecular Chaperone Molecule AIP Results in a Novel Severe Multisystem Disease Defined by Defective Proteostasis

Children born with deleterious biallelic variants of the chaperone aryl hydrocarbon receptor interacting protein (AIP) have a novel pediatric metabolic disease presenting a severe, complex clinical phenotype characterized by failure to develop following birth. Analysis of Aip knockout mouse embryonic fibroblasts and patient-derived dermal fibroblasts revealed that AIP was required to support proteostasis; including proteasome activity, induction of autophagy and lysosome function. aip knockout zebrafish, recapitulated the phenotype of the children; dying at an early stage of development when autophagy is required to adapt to periods of starvation. Our results demonstrate that AIP plays a crucial role in initiating autophagy and maintaining proteostasis in vitro and in vivo. One Sentence SummaryHomozygous loss of the chaperone AIP results in a novel pediatric disease exhibiting multiple features of a lysosomal storage disease.

molecular biology↗

bioRxiv2022

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

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.

developmental biology↗

bioRxiv2020

Quantitative lineage analysis identifies a long-term progenitor niche for the hepato-pancreato-biliary organ system

Single cell-based studies have revealed tremendous cellular heterogeneity in stem cell and progenitor compartments, suggesting continuous differentiation trajectories with intermixing of cells at various states of lineage commitment and notable degree of plasticity during organogenesis1-5. The hepato-pancreato-biliary organ system relies on a small endoderm progenitor compartment that gives rise to a variety of different adult tissues, including liver, pancreas, gallbladder, and extra-hepatic bile ducts6, 7. Experimental manipulation of various developmental signals in the mouse embryo underscored an important cellular plasticity in this embryonic territory6, 8. This is also reflected in the existence of human genetic syndromes as well as congenital or environmentally-caused human malformations featuring multiorgan phenotypes in liver, pancreas and gallbladder6, 8. Nevertheless, the precise lineage hierarchy and succession of events leading to the segregation of an endoderm progenitor compartment into hepatic, biliary, and pancreatic structures are not yet established. Here, we combine computational modelling approaches with genetic lineage tracing to assess the tissue dynamics accompanying the ontogeny of the hepato-pancreato-biliary organ system. We show that a long-term multipotent progenitor domain persists at the border between liver and pancreas, even after pancreatic fate is specified, contributing to the formation of several organ derivatives, including the liver. Moreover, using single-cell RNA sequencing we define a specialized niche that possibly supports such long-term cell fate plasticity.

developmental biology↗