A5007552874- Pluripotent Stem Cells Research
- RNA Research and Splicing
- MicroRNA in disease regulation
- RNA modifications and cancer
- Mitochondrial Function and Pathology
- Animal Genetics and Reproduction
- Cell death mechanisms and regulation
- CRISPR and Genetic Engineering
- Silicon Effects in Agriculture
- Circular RNAs in diseases
- Congenital heart defects research
- RNA Interference and Gene Delivery
- Autophagy in Disease and Therapy
- Single-cell and spatial transcriptomics
- Aluminum toxicity and tolerance in plants and animals
- Hippo pathway signaling and YAP/TAZ
- Plant Micronutrient Interactions and Effects
- Cancer-related molecular mechanisms research
- Genomics and Chromatin Dynamics
- TGF-β signaling in diseases
- Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Biomedical Ethics and Regulation
- Lipid metabolism and biosynthesis
- Plant Disease Resistance and Genetics
- RNA and protein synthesis mechanisms
Centre for Genomic Regulation
2019-2024
Imperial College London
2011-2023
Hammersmith Hospital
2011-2023
Lung Institute
2020
National Institutes of Health
2014
British Heart Foundation
2013-2014
Spanish National Centre for Cardiovascular Research
2009-2011
Universidad Autónoma de Madrid
2009
Universidad Complutense de Madrid
2005-2007
Linear ubiquitination is crucial for innate and adaptive immunity. The linear ubiquitin chain assembly complex (LUBAC), consisting of HOIL-1, HOIP, SHARPIN, the only known ligase that generates linkages. HOIP catalytically active LUBAC component. Here, we show both constitutive Tie2-Cre-driven deletion lead to aberrant endothelial cell death, resulting in defective vascularization embryonic lethality at midgestation. Ablation tumor necrosis factor receptor 1 (TNFR1) prevents defects, death...
Highlights•Defective ESCs are eliminated at the onset of differentiation by wild-type cells•Elimination unfit cells is apoptosis dependent and mediated secreted factors•Higher c-Myc levels established in cocultured with cells•c-Myc overexpression induces a competitive advantage ESCsSummaryA fundamental question developmental biology whether there mechanisms to detect stem mutations that, although not adversely affecting viability, would compromise their ability contribute further...
Oocytes are among the longest-lived cells in body and need to preserve their cytoplasm support proper embryonic development. Protein aggregation is a major threat for intracellular homeostasis long-lived cells. How oocytes cope with protein during extended life unknown. Here, we find that mouse accumulate aggregates specialized compartments named endolysosomal vesicular assemblies (ELVAs). Combining live-cell imaging, electron microscopy, proteomics, found ELVAs non-membrane-bound composed...
Transition from maternal to embryonic transcriptional control is crucial for embryogenesis. However, alternative splicing regulation during this process remains understudied. Using transcriptomic data human, mouse, and cow preimplantation development, we show that the stage of zygotic genome activation (ZGA) exhibits highest levels exon skipping diversity reported any cell or tissue type. Much temporary, leads disruptive noncanonical isoforms, occurs in genes enriched DNA damage response...
The changes that drive differentiation facilitate the emergence of abnormal cells need to be removed before they contribute further development or germline. Consequently, in mice lead-up gastrulation, ∼35% embryonic are eliminated. This elimination is caused by hypersensitivity apoptosis, but how it regulated poorly understood. Here, we show upon exit naive pluripotency, mouse stem lower their mitochondrial apoptotic threshold, and this increases sensitivity cell death. We demonstrate...
Mammalian primed pluripotent stem cells have been shown to be highly susceptible cell death stimuli due their low apoptotic threshold, but how this threshold is regulated remains largely unknown. Here we identify microRNA (miRNA)-mediated regulation as a key mechanism controlling apoptosis in the post-implantation epiblast. Moreover, found that three miRNA families, miR-20, miR-92, and miR-302, control mitochondrial machinery by fine-tuning levels of expression proapoptotic protein BIM....
Embryonic pluripotency in the mouse is established and maintained by a gene-regulatory network under control of core set transcription factors that include octamer-binding protein 4 (Oct4; official name POU domain, class 5, factor 1, Pou5f1), sex-determining region Y (SRY)-box containing gene 2 (Sox2), homeobox Nanog. Although this largely conserved eutherian mammals, very little information available regarding its evolutionary conservation other vertebrates. We have compared embryonic...
The structural complexity of the vertebrate brain is mirrored by its unparalleled transcriptome complexity. In particular, two post-transcriptional processes, alternative splicing and RNA editing, greatly diversify transcriptomes. Here we report a close connection between these processes: show A-to-I editing in Nova1, key brain-specific regulator splicing. Nova1 levels increase during embryonic development mouse chicken brains significant variation across postnatal regions. Evolutionary...
Nodal/activin signaling plays a key role in anterior-posterior (A-P) axis formation by inducing the anterior visceral endoderm (AVE), extraembryonic center that initiates patterning embryo. Here we provide direct evidence mitogen-activated protein kinase (MAPK) p38 regulates AVE specification through crosstalk with pathway. We show activation is directly stimulated and fails to be maintained upon inhibition of this pathway both vivo vitro. In turn, strengthens Nodal response phosphorylating...
Understanding the regulatory interactions that control gene expression during development of novel tissues is a key goal evolutionary developmental biology. Here, we show Mbnl3 has undergone striking process specialization in eutherian mammals resulting emergence placental function for gene. belongs to family RNA-binding proteins whose members regulate multiple aspects RNA metabolism. We find that, eutherians, while both and its paralog Mbnl2 are strongly expressed placenta, been lost from...
At the time of implantation mouse embryo is composed three tissues epiblast, trophectoderm and primitive endoderm. As development progresses epiblast goes on to form foetus whilst endoderm give rise extra-embryonic structures with important roles in patterning nutrition. Dramatic changes gene expression occur during early these require regulation at different levels. miRNAs are small non coding RNAs that have emerged over last decade as post-transcriptional repressors expression. The played...
In the mouse blastocyst, Eomes and Cdx2 are critical for establishing trophoectoderm, precursor of placenta. To better understand how trophoectoderm lineage arose in mammals during evolution, we examined expression their orthologues pregastrulation chick embryo found that, while both genes expressed extraembryonic tissues, temporal pattern differs from what occurs mouse. Moreover, failed to detect other specific regions chick. Also unlike mouse, is primordial germ cells. Finally, conserved...
Abstract Cell competition is emerging as a quality control mechanism that eliminates unfit cells in wide range of settings from development to the adult. However, nature normally eliminated by cell and what triggers their elimination remains poorly understood. In mouse, prior gastrulation 35% epiblast are eliminated. Here we have performed single transcriptional profiling these find they show hallmarks mitochondrial defects. We demonstrate defects common different loser types manipulating...
MicroRNAs (miRNAs) are important regulators of embryonic stem cell (ESC) biology, and their study has identified key regulatory mechanisms. To find novel pathways regulated by miRNAs in ESCs, we undertook a bioinformatics analysis gene differently expressed the absence due to deletion Dicer, which encodes an RNase that is essential for synthesis miRNAs. One pathway stood out was Ca2+ signaling. Interestingly, found Dicer-/- ESCs had no difference basal cytoplasmic levels but were...
Abstract The changes that drive differentiation create a large potential for the emergence of abnormal cells need to be removed before they contribute further development or germline. This removal is in part achieved by becoming hypersensitive death upon exit naïve pluripotency. What causes this change apoptotic response unknown. Here we identify it controlled regulator mitochondrial dynamics DRP1. We show mouse, pluripotent have fragmented mitochondria due high DRP1-mediated fission, but...
ABSTRACT The transition from maternal to embryonic transcriptional control is a crucial step in embryogenesis. However, how alternative splicing regulated during this process and it contributes early development unknown. Using transcriptomic data pre-implantation stages of human, mouse cow, we show that the stage zygotic genome activation (ZGA) exhibits highest levels exon skipping diversity reported for any cell or tissue type. Interestingly, much temporary, leads disruptive non-canonical...
Abstract The eutherian placenta is a major site for parental genetic conflict. Here, we identify the X-linked Mbnl3 gene as novel player in this dispute. belongs to an RNA binding protein family whose members regulate alternative splicing and other aspects of metabolism association with cellular differentiation. We find that, eutherians, has become specifically expressed undergone accelerated sequence evolution leading changes its specificities. Although molecular roles are partly redundant...