MRC Mouse Network Meeting – Jan 2012
Developmental Anomalies
Consortium
Nick Greene
UCL Institute of Child Health
Developmental anomalies/birth defects
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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
Genetic
causes
Developmental
Anomalies
Consortium
Developmental
mechanisms
ICH/UCL/GOSH
GOSgene, UCL Genomics
Research teams working on defects of
CNS, palate, skull, eye, kidney, heart, gut
Links to Centre for Advanced Bioimaging
Novel therapies
Gene & stem cell therapies, tissue
engineering, small molecules (UCL)
Clinical trials
Clinical Research Facility (GOSH), Clinical
Trials Unit (UCL)
Population
studies
MRC Centre of Epidemiology for
Childhood Disease
Developmental Anomalies Consortium
Skull
Pauws
Cerebral
cortex
Jacques
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
Heart
Riley
Enteric nervous system
Burns
Human
35 days
Kidney
Long, Winyard
Imaging Lythogoe (Centre for Advanced Bioimaging)
Gonad, adrenal
Achermann
Embryos from Human Developmental
Biology Resource
Research Plans
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Selection of genes:
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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:
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Culture methods:
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Gross morphology, histological analysis
Gene expression (lacZ staining, in situ hybridisation, immunohistochemistry)
Micro MRI (also micro-CT or OPT in selected models)
Whole embryo culture
- Organotypic culture
- Stem cell culture
Genomic, molecular & cellular analysis
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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)
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Mechanism to identify to identify birth defects in pre-natal lethal
models?
Research plan
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Selection of genes
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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
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Developmental phenotypes examined by teams focused on
particular organ systems
Analysis of tissue & stage-specific gene function
Gene-environment interaction (eg, nutritional folate deficiency)
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Functional/mechanistic analysis
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Development of biomarkers and therpeutic interventions
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Externally visible defects
Coloboma
Phocomelia
Synpolydactyly
Craniofacial disorder
Holoprosencephaly
with cyclopia
Cleft lip/palate
Spina bifida
Internal
organ defects
Polycystic kidneys
Diaphragmatic hernia
Hirschsprung’s disease
Tracheooesophageal
fistula
Ventricular septal defect