MRC Mouse Network Meeting – Jan 2012 Developmental Anomalies Consortium Nick Greene UCL Institute of Child Health
Developmental anomalies/birth defects • Defects of structure (malformations) • Present at birth (congenital) • Originate during pregnancy (usually early) • Can be caused by genetic and/or environmental factors Environmental Genetic
What is the size of the problem? • 1 in every 40 infants has a birth defect • 360,000/year new birth defects in Europe • 286,000 progress beyond 1 week of age • ~ 40% of children at GOSH have a birth defect Dolk et al, 2010, Adv Exp Med Biol 686, 349
Aims & Objectives Analyse IMPC mouse models in order to: • Understand the genetic and developmental origin of birth defects • Establish tools for translation to clinical diagnosis, therapy and prevention of human birth defects.
Birth defects research: a multi-disciplinary approach ICH/UCL/GOSH GOSgene, UCL Genomics Developmental Anomalies Consortium Gene & stem cell therapies, tissue engineering, small molecules (UCL) Geneticcauses Clinical Research Facility (GOSH), Clinical Trials Unit (UCL) Developmentalmechanisms MRC Centre of Epidemiology for Childhood Disease Novel therapies Clinical trials Populationstudies
Developmental Anomalies Consortium Cerebral cortex Jacques Skull Pauws Palate Stanier Branchial arch arteries Scambler Choroid plexus Ferretti Neural tube (Brain & spinal cord) Copp, Greene Pituitary Martinez-Barbera, Dattani Syndromes (Ciliopathies) Beales, Mitchison, Hammond Eye Sowden Gonad, adrenal Achermann Heart Riley Human 35 days Kidney Long, Winyard Enteric nervous system Burns Embryos from Human Developmental Biology Resource Imaging Lythogoe (Centre for Advanced Bioimaging)
Research Plans • Selection of genes: • Relevance to aims & objectives of Consortium • Preliminary data to suggest role in birth defects (eg. altered expression in existing model, candidates for human conditions from patient screens) • Lack of existing knockout or conditional
Consortium activity within the Network Experimental approaches for analysis of prority gene models • Phenotyping: • Gross morphology, histological analysis • Gene expression (lacZ staining, in situ hybridisation, immunohistochemistry) • Micro MRI (also micro-CT or OPT in selected models) • Culture methods: • Whole embryo culture - Organotypic culture - Stem cell culture • Genomic, molecular & cellular analysis • Many Cre-deletor lines available UCL/ICH • Transcriptomics (UCL Genomics) - FACS core facilty (eg, cell sorting for microarray) Additional models from other Consortia • Expected that birth defects will arise in additional models, many will be pre-natal lethal (homozygote sub-viable) • Phenotypes include: • Externally visible defects (NTDs, cleft palate, craniofacial & limb) • Internal organ defects (ENS, kidney, heart, tracheo-oesophageal fistula) • Mechanism to identify to identify birth defects in pre-natal lethal models?
Research plan • Selection of genes • Relevance to aims & objectives of Consortium • Preliminary data to suggest role in birth defects (eg. altered expression in existing model, candidates for human conditions from patient screens) • Lack of existing knockout or conditional • Developmental phenotypes examined by teams focused on particular organ systems • Analysis of tissue & stage-specific gene function • Gene-environment interaction (eg, nutritional folate deficiency) • Functional/mechanistic analysis • Development of biomarkers and therpeutic interventions
Externally visible defects Craniofacial disorder Coloboma Synpolydactyly Holoprosencephaly with cyclopia Phocomelia Cleft lip/palate Spina bifida
Internal organ defects Polycystic kidneys Diaphragmatic hernia Ventricular septal defect Tracheo-oesophageal fistula Hirschsprung’s disease