A5038462165- Retinal Development and Disorders
- Pluripotent Stem Cells Research
- melanin and skin pigmentation
- Genetic and Kidney Cyst Diseases
- Animal Genetics and Reproduction
- Ocular Disorders and Treatments
- Reproductive Biology and Fertility
- Protist diversity and phylogeny
- CRISPR and Genetic Engineering
- Renal and related cancers
- Genetics, Aging, and Longevity in Model Organisms
- Cell Image Analysis Techniques
- Genetic Syndromes and Imprinting
- Hedgehog Signaling Pathway Studies
- Biochemical Analysis and Sensing Techniques
- Molecular Biology Techniques and Applications
- RNA Interference and Gene Delivery
- Prenatal Screening and Diagnostics
- Virus-based gene therapy research
- RNA modifications and cancer
- Fetal and Pediatric Neurological Disorders
- Photoreceptor and optogenetics research
- Hair Growth and Disorders
- Endoplasmic Reticulum Stress and Disease
- Chromosomal and Genetic Variations
Institute of Genetics and Cancer
2012-2022
University of Edinburgh
2012-2022
Western General Hospital
2006-2022
The Queen's Medical Research Institute
2018
Great Ormond Street Hospital
2018
University College London
2018
MRC Human Genetics Unit
2007-2014
Institutt for Grafiske Medier
2014
Medical Research Council
2003-2011
MRC Centre for Reproductive Health
1993-1999
The presence of ribonucleotides in genomic DNA is undesirable given their increased susceptibility to hydrolysis. Ribonuclease (RNase) H enzymes that recognize and process such embedded are present all domains life. However, unicellular organisms as budding yeast, they not required for viability or even efficient cellular proliferation, while humans, RNase H2 hypomorphic mutations cause the neuroinflammatory disorder Aicardi-Goutières syndrome. Here, we report an essential enzyme mice,...
Markers of cell cycle stage allow estimation dynamics in culture and during embryonic development. The Fucci system incorporates genetically encoded probes that highlight G1 S/G2/M phases the allowing live imaging. However available mouse models incorporate are beset by problems with transgene inactivation, varying expression level, lack conditional potential and/or need to maintain separate transgenes—there is no transgenic model solves all these problems. To address shortfalls we...
Defects in cilia formation and function result a range of human skeletal visceral abnormalities. Mutations several genes have been identified to cause proportion these disorders, some which display genetic (locus) heterogeneity. Mouse models are valuable for dissecting the genes, as well more detailed analysis underlying developmental defects. The short-rib polydactyly (SRP) group disorders among most severe phenotypes caused by dysfunction. We mapped disease locus from two siblings affected...
Defects in cilium and centrosome function result a spectrum of clinically-related disorders, known as ciliopathies. However, the complex molecular composition these structures confounds functional dissection what any individual gene product is doing under normal disease conditions. As part an siRNA screen for genes involved mammalian ciliogenesis, we others have identified conserved centrosomal protein Azi1/Cep131 required cilia formation, supporting previous Danio rerio Drosophila...
Abstract Patterns of growth and cell movement in the developing adult corneal epithelium were investigated by analysing clonal patches LacZ ‐expressing cells chimeric X‐inactivation mosaic mice. It was found that proliferation throughout basal during embryogenesis early postnatal life creates a disordered pattern + clones contrasts with patterns striping produced later embryonic stages retinal pigmented development. The is replaced first 12 weeks an ordered radial stripes or sectors reflects...
The cilia and cell cycles are inextricably linked. Centrioles in the basal body of nucleate ciliary axoneme sequester pericentriolar matrix (PCM) at centrosome to organize mitotic spindle. Cilia themselves respond growth signals, prompting resorption cycle re-entry. We describe a fluorescent biosensor allowing live imaging progression assembly disassembly kinetics cells inducible mice. define relation stage with single-cell resolution explore intercellular heterogeneity kinetics. In all...
Bands of colour extending laterally from the dorsal to ventral trunk are a common feature mouse chimeras. These stripes were originally taken as evidence directed dorsoventral migration melanoblasts (the embryonic precursors melanocytes) they colonize developing skin. Depigmented 'belly spots' in mice with mutations receptor tyrosine kinase Kit thought represent failure this colonization, either due impaired or proliferation. Tracing single melanoblast clones, however, has revealed diffuse...
Palmitoylation is a key post-translational modification mediated by family of DHHC-containing palmitoyl acyl-transferases (PATs). Unlike other lipid modifications, palmitoylation reversible and thus often regulates dynamic protein interactions. We find that the mouse hair loss mutant, depilated, (dep) due to single amino acid deletion in PAT, Zdhhc21, resulting mislocalization activity. examined expression Zdhhc21 skin it restricted specific lineages. Loss function results delayed shaft...
Molecular chaperones promote the folding and macromolecular assembly of a diverse set 'client' proteins. How ubiquitous chaperone machineries direct their activities towards specific sets substrates is unclear. Through use mouse genetics, imaging quantitative proteomics we uncover that ZMYND10 novel co-chaperone confers specificity for FKBP8-HSP90 complex axonemal dynein clients required cilia motility. Loss perturbs chaperoning heavy chains, triggering broader degradation motor subunits. We...
Intraflagellar transport (IFT) is a highly conserved mechanism for motor-driven of cargo within cilia, but how this selectively transported to cilia unclear. WDR35/IFT121 component the IFT-A complex best known its role in ciliary retrograde transport. In absence WDR35, small mutant form fail enrich diverse classes membrane proteins. Wdr35 mouse mutants, non-core components are degraded and core accumulate at base. We reveal deep sequence homology WDR35 other subunits α ß′ COPI coatomer...
Mutations in the LIM-homeodomain transcription factor LMX1B cause nail-patella syndrome, an autosomal dominant pleiotrophic human disorder which nail, patella and elbow dysplasia is associated with other skeletal abnormalities variably nephropathy glaucoma. It thought to be a haploinsufficient disorder. Studies mouse have shown that during development Lmx1b controls limb dorsal-ventral patterning also required for kidney eye development, midbrain-hindbrain boundary establishment...
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Response to painful stimuli is susceptible genetic variation. Numerous loci have been identified which contribute this variation, one of which, MC1R, better known as a gene involved in mammalian hair colour. MC1R G protein-coupled receptor expressed melanocytes and elsewhere mice lacking yellow hair, whilst humans with variant protein red hair. Previous work has found differences acute pain perception, response analgesia mutations or variants MC1R.We tested responses noxious non-noxious...
The melanocortin receptor, MC1R, is a key regulator of pigmentation in mammals, and necessary for production dark eumelanin pigment. Human MC1R variants with reduced or absent function are associated red hair; mouse mutants result yellow fur. Previous reports indicate differences between human receptors their sensitivity to, requirement for, alphaMSH agonist. We have generated transgenic model which coat mediated solely by MC1R. Although the hair pigment pattern superficially normal, we show...
Isocitrate dehydrogenase (IDH) is an enzyme required for the production of α-ketoglutarate from isocitrate. IDH3 generates NADH used in mitochondria ATP production, and a tetramer made up two α, β γ subunit. Loss function missense mutations both IDH3A andIDH3B have previously been implicated families exhibiting retinal degeneration. Using mouse models we investigated role disease mitochondrial function. We identified mice with late-onset degeneration screen ageing carrying ENU-induced...
We previously found a dominant mutation, Rwhs, causing white spots on the retina accompanied by retinal folds. Here we identify mutant gene to be Tmem98. In humans, mutations in orthologous cause nanophthalmos. modeled these mice and characterized eye phenotypes of Rwhs.The Rwhs mutation was identified missense Tmem98 genetic mapping sequencing. The human TMEM98 nanophthalmos were made mouse CRISPR-Cas9. Eyes examined indirect ophthalmoscopy retinas imaged using camera. Electroretinography...
A mouse mutant identified during a recessive N-ethyl-N-nitrosourea (ENU) mutagenesis screen exhibited ocular hemorrhaging resulting in blood-filled orbit, and hence was named "redeye." We aimed to identify the causal mutation redeye, evaluate it as model for diabetic retinopathy (DR).The causative gene redeye by haplotype mapping followed exome sequencing. Glucose tolerance tests, detailed histologic immunofluorescence analyses, vascular permeability assays were performed determine affect of...
Substrate- and ligand-induced conformational changes were studied in a series of thiol-modified derivatives rabbit muscle creatine kinase that retained different amounts enzymic activity. The results indicate the 'reactive' thiol group enzyme is required for associated with formation 'transition-state analogue' complex.
Mp is an irradiation-induced mouse mutation associated with microphthalmia, micropinna and hind limb syndactyly. We show that caused by a 660 kb balanced inversion on chromosome 18 producing reciprocal 3-prime gene fusion events involving Fbn2 Isoc1. The Isoc1-Fbn2 (Isoc1(Mp)) mRNA has frameshift early stop codon resulting in nonsense mediated decay. Homozygous deletions of Isoc1 do not support significant developmental role for this gene. Fbn2-Isoc1 (Fbn2 (Mp)) predicted protein consists...