1. Developmental Anomalies Consortium Nick Greene UCL Institute of Child Health MRC Mouse Network Meeting – Jan 2012

2. 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 Genetic Environmental

3. 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

4. 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.

5. Birth defects research: a multi-disciplinary approach Genetic causes Developmental mechanisms Novel therapies Clinical trials Population studies MRC Centre of Epidemiology for Childhood Disease Clinical Research Facility (GOSH), Clinical Trials Unit (UCL) Research teams working on defects of CNS, palate, skull, eye, kidney, heart, gut Links to Centre for Advanced Bioimaging GOSgene, UCL Genomics Developmental Anomalies Consortium Gene & stem cell therapies, tissue engineering, small molecules (UCL) ICH/UCL/GOSH

6. Developmental Anomalies Consortium Human 35 days Eye Sowden Skull Pauws Palate Stanier Branchial arch arteries Scambler Heart Riley Pituitary Martinez-Barbera, Dattani Kidney Long, Winyard Choroid plexus Ferretti Neural tube (Brain & spinal cord) Copp, Greene Gonad, adrenal Achermann Syndromes (Ciliopathies) Beales, Mitchison, Hammond Embryos from Human Developmental Biology Resource Enteric nervous system Burns Cerebral cortex Jacques Imaging Lythogoe (Centre for Advanced Bioimaging)

7. 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

8. 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?

9. 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

10. Holoprosencephaly with cyclopia Phocomelia Synpolydactyly Craniofacial disorder Externally visible defects Spina bifida Cleft lip/palate Coloboma

11. Internal organ defects Hirschsprung’s disease Tracheo- oesophageal fistula Ventricular septal defect Polycystic kidneys Diaphragmatic hernia