Developmental Anomalies Consortium

Nick GreeneUCL Institute of Child Health

MRC Mouse Network Meeting – Jan 2012

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

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

Geneticcauses

Developmentalmechanisms

Novel therapies

Clinical trials

Populationstudies

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

Developmental Anomalies Consortium

Human35 days

Eye Sowden

SkullPauws Palate

Stanier Branchial arch arteries Scambler

HeartRiley

PituitaryMartinez-Barbera,

Dattani

KidneyLong, Winyard

Choroid plexusFerretti Neural tube

(Brain & spinal cord)

Copp, Greene

Gonad, adrenal Achermann

Syndromes (Ciliopathies)

Beales, Mitchison, Hammond

Embryos from Human Developmental Biology Resource

Enteric nervous systemBurns

Cerebral cortex

Jacques

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 NetworkExperimental 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

Holoprosencephaly with cyclopia

Phocomelia Synpolydactyly

Craniofacial disorder

Externally visible defects

Spina bifidaCleft lip/palate

Coloboma

Internal organ defects

Hirschsprung’s disease Tracheo-oesophageal

fistula

Ventricular septal defect

Polycystic kidneys

Diaphragmatic hernia