A5036989854- Neuroscience and Neuropharmacology Research
- Pluripotent Stem Cells Research
- Glioma Diagnosis and Treatment
- Memory and Neural Mechanisms
- Neurogenesis and neuroplasticity mechanisms
- Nerve injury and regeneration
- Neuroinflammation and Neurodegeneration Mechanisms
- Congenital heart defects research
- MicroRNA in disease regulation
- Developmental Biology and Gene Regulation
- Pancreatic function and diabetes
- Receptor Mechanisms and Signaling
- Regulation of Appetite and Obesity
- Renal and related cancers
- Bone Metabolism and Diseases
- Cancer Cells and Metastasis
- Adipose Tissue and Metabolism
- Axon Guidance and Neuronal Signaling
- Biochemical Analysis and Sensing Techniques
- Neuroendocrine regulation and behavior
- Cancer, Lipids, and Metabolism
- Metabolism, Diabetes, and Cancer
- TGF-β signaling in diseases
- Single-cell and spatial transcriptomics
- Pregnancy and preeclampsia studies
University College London
2004-2025
CRUK Lung Cancer Centre of Excellence
2021-2025
London Cancer
2022-2025
Royal College of Surgeons of England
2022
MRC London Institute of Medical Sciences
2017
Imperial College London
2011-2017
Hammersmith Hospital
1996-2014
Medical Research Council
2002-2011
MRC Clinical Trials Unit at UCL
2009
Diabetes Australia
2008
Recent evidence suggests that alterations in insulin/insulin-like growth factor 1 (IGF1) signaling (IIS) can increase mammalian life span. For example, several mouse mutants, impairment of the hormone (GH)/IGF1 axis increases span and also insulin sensitivity. However, intracellular route to altered aging remains unclear. We therefore measured mice lacking either receptor substrate (IRS) or 2, major effectors IIS receptors. Our provisional results indicate female Irs1-/- are long-lived....
Hypothalamic AMP-activated protein kinase (AMPK) has been suggested to act as a key sensing mechanism, responding hormones and nutrients in the regulation of energy homeostasis. However, precise neuronal populations cellular mechanisms involved are unclear. The effects long-term manipulation hypothalamic AMPK on balance also unknown. To directly address such issues, we generated POMCα2KO AgRPα2KO mice lacking AMPKα2 proopiomelanocortin– (POMC-) agouti-related protein–expressing...
The homeobox gene Hex is expressed in the anterior visceral endoderm (AVE) and rostral definitive of early mouse embryos. Later, transcripts are detected liver, thyroid endothelial precursor cells. A null mutation was introduced into locus by homologous recombination embryonic stem mutant embryos exhibit varying degrees truncation as well liver dysplasia. diverticulum formed but migration hepatocytes septum transversum fails to occur. Development arrested at bud stage 9.5 dpc. Brain defects...
Schwann cell dedifferentiation from a myelinating to progenitor-like underlies the remarkable ability of peripheral nerves regenerate following injury. However, molecular identity differentiated and dedifferentiated states in vivo has been elusive. Here, we profiled cells acutely purified intact wound distal regions severed nerves. Our analysis reveals novel facets response, including acquisition mesenchymal traits Myc module. Furthermore, constitute different populations, with displaying...
Insulin receptor substrate 2 (Irs2) plays complex roles in energy homeostasis. We generated mice lacking Irs2 β cells and a population of hypothalamic neurons (RIPCreIrs2KO), all (NesCreIrs2KO), proopiomelanocortin (POMCCreIrs2KO) to determine the role CNS cell. RIPCreIrs2KO displayed impaired glucose tolerance reduced cell mass. Overt diabetes did not ensue, because escaping Cre-mediated recombination progressively populated islets. NesCreIrs2KO hyperphagia, obesity, increased body length,...
A loss-of-function mutation in the mouse delta-like3 (Dll3) gene has been generated following targeting, and results severe axial skeletal defects. These defects, which consist of highly disorganised vertebrae costal are similar to those associated with Dll3-dependent pudgy mutant spondylocostal dysplasia (MIM 277300) humans. This study demonstrates that Dll3neo Dll3pu functionally equivalent alleles respect dysplasia, we suggest three human DLL3 mutations also null allele. Our phenotypic...
The anterior visceral endoderm (AVE) of the mouse embryo is a specialised extra-embryonic tissue that essential for patterning embryo. It characterised by expression markers such as Hex, Cerberus-like and Lhx1. At pre-gastrula stages, cells AVE are initially located at distal tip embryo, but they then move unilaterally to future anterior. This movement converting existing proximodistal axis into an anteroposterior axis. To investigate this process, we developed culture system capable imaging...
PI3K signaling is thought to mediate leptin and insulin action in hypothalamic pro-opiomelanocortin (POMC) agouti-related protein (AgRP) neurons, key regulators of energy homeostasis, through largely unknown mechanisms. We inactivated either p110α or p110β catalytic subunits these neurons demonstrate a dominant role for the latter homeostasis regulation. In POMC inactivation prevented insulin- leptin-stimulated electrophysiological responses. POMCp110β null mice exhibited central resistance,...
Glioblastomas (GBM) are aggressive and therapy-resistant brain tumours, which contain a subpopulation of tumour-propagating glioblastoma stem-like cells (GSC) thought to drive progression recurrence. Diffuse invasion the parenchyma, including along preexisting blood vessels, is leading cause therapeutic resistance, but mechanisms remain unclear. Here, we show that ephrin-B2 mediates GSC perivascular invasion. Intravital imaging, coupled with mechanistic studies in murine GBM models...
Abstract Adult neural stem cells (NSCs) must tightly regulate quiescence and proliferation. Single-cell analysis has suggested a continuum of cell states as NSCs exit quiescence. Here we capture characterize in vitro primed quiescent identify LRIG1 an important regulator. We show that BMP-4 signaling induces dormant non-cycling state (d-qNSCs), whereas combined BMP-4/FGF-2 distinct poised for cycle re-entry. Primed (p-qNSCs) are defined by high levels CD9, well interferon response signature,...
Abstract Glioblastomas are hierarchically organised tumours driven by glioma stem cells that retain partial differentiation potential. Glioma maintained in specialised microenvironments, but whether, or how, they undergo lineage progression outside of these niches remains unclear. Here we identify the white matter as a differentiative niche for glioblastomas with oligodendrocyte competency. Tumour contact acquire pre-oligodendrocyte fate, resulting decreased proliferation and invasion....
Glioblastoma (GBM) recurrence originates from invasive margin cells that escape surgical debulking, but to what extent these resemble their bulk counterparts remains unclear. Here, we generated three immunocompetent somatic GBM mouse models, driven by subtype-associated mutations, compare matched and cells. We find that, regardless of tumors converge on common sets neural-like cellular states. However, have distinct biology. Injury-like programs associated with immune infiltration dominate...
The anterior visceral endoderm (AVE) is an extra-embryonic tissue required for specifying pattern in the mouse embryo. AVE induced at distal tip of 5.5 dpc embryo and then migrates to prospective anterior, where it imparts identity upon underlying epiblast (the that gives rise proper). Little known about how what directs its migration. In this paper, we describe essential role another tissue, ectoderm (ExE), patterning epiblast. Removal ExE pre-gastrulation embryos leads ectopic formation, a...
The homeobox gene Hesx1/HESX1 has been implicated in the establishment of anterior pattern central nervous system (CNS) a number vertebrate species. Its role pituitary development documented through loss-of-function studies mouse. A homozygous missense point mutation resulting single amino acid substitution, Arg160Cys (R160C), is associated with heritable form human condition septo-optic dysplasia (SOD). We have examined phenotype affected members this pedigree more detail and demonstrate...
Defective insulin secretion in response to glucose is an important component of the β cell dysfunction seen type 2 diabetes. As mitochondrial oxidative phosphorylation plays a key role glucose-stimulated (GSIS), oxygen-sensing pathways may modulate release. The von Hippel–Lindau (VHL) protein controls degradation hypoxia-inducible factor (HIF) coordinate cellular and organismal responses altered oxygenation. To determine this pathway controlling release from pancreatic cells, we generated...
LKB1 is a ‘master’ protein kinase implicated in the regulation of metabolism, cell proliferation, polarity and tumorigenesis. However, long-term role hepatic function unknown. In present study, it shown that plays key liver cellular architecture metabolism. We report liver-specific deletion mice leads to defective canaliculi bile duct formation, causing impaired acid clearance subsequent accumulation acids serum liver. Concomitant with this, was found majority BSEP (bile salt export pump)...
ABSTRACT One of the earliest markers anterior asymmetry in vertebrate embryos is transcription factor Hex. We find that Hex a transcriptional repressor can be converted to an activator by fusing full length two copies minimal activation domain VP16 together with flexible hinge region λ (Hex-λVP2). Retention entire open reading frame allows one examine function without disrupting potential protein-protein interactions. Expression Hex-λVP2 Xenopus inhibits expression marker Cerberus and...
Cited1 is a transcriptional cofactor that interacts with Smad4, estrogen receptors α and β, TFAP2, CBP/p300. It expressed in restricted manner the embryo as well extraembryonic tissues during embryonic development. In this study we report engineering of loss-of-function mutation mouse. null mutants show growth restriction at 18.5 days postcoitum, most them die shortly after birth. Half heterozygous females, i.e., those carry paternally inherited wild-type allele, are similarly affected....
The anterior visceral endoderm (AVE), a signalling centre within the simple epithelium of (VE), is required for anterior-posterior axis specification in mouse embryo. AVE cells migrate directionally VE, thereby properly positioning future embryo and orientating primary body axis. consistently come to an abrupt stop at border between epiblast extra-embryonic ectoderm, which represents end-point their proximal migration. Little known about underlying basis this barrier how surrounding VE...
During development, the growth of embryo must be coupled to its patterning ensure correct and timely morphogenesis. In mouse embryo, migration anterior visceral endoderm (AVE) prospective establishes anterior-posterior (A-P) axis. By analysing distribution cells in S phase, M phase G2 from time just prior AVE until 18 hours after movement, we show that there is no evidence for differential proliferation along A-P axis embryo. Rather, have identified as movements are being initiated, epiblast...