Key Research Areas 

• Embryonic development
• Congenital heart disease
• Genetic and environmental causes of birth defects

Research Overview 

 The Embryology Laboratory is identifying the genetic and environmental causes of birth defects, including congenital heart disease. Gene mutations are being identified in patients using whole genome sequencing and mouse models are being developed to understand how genetic mutations and environmental factors impact on embryogenesis. Research projects underway in the Embryology Laboratory, led by Professor Sally Dunwoodie:

1. Genetic causes of congenital malformation

Families with congenital malformation are being recruited and gene mutations are being identified using whole genome sequencing, and in-house bioinformatics. Some mutations occur in genes known to cause congenital malformation. These mutations are tested for pathogenicity using an array of in vitro assays. Many mutations arise in “new” genes and thus their relevance to congenital malformation is being established in preclinical models, such as the mouse.
We have discovered that:

• mutations in DLL3, MESP2, LFNG, HES7, TBX6, or RIPPLY2 cause vertebral defects
• mutations in KYNU, HAAO or NADSYN1 causing multiple congenital malformations

2. Environmental causes of congenital malformation

We are determining if risk factors associated with congenital malformation in humans, disrupt embryogenesis in mice. Moreover, a number of risk factors lead to hypoxia in the embryo; therefore, we use short-term gestational hypoxia to disrupt embryogenesis and determine the molecular and cellular sequelae.
We have discovered in mice that:

• hypoxia inhibits fibroblast growth factor (FGF) signalling, which disrupts heart and vertebral formation
• hypoxia induces the unfolded protein response (UPR) and in doing so inhibits FGF signalling

3. Gene-Environment interaction (GxE) as a cause of congenital malformation

A genetic predisposition to a birth defect might, in combination with an adverse environmental stress, disrupt embryogenesis. In mouse, we are exploring the extent to which GxE disrupts embryogenesis.
We have discovered in mice that:

• A genetic predisposition interacts with environmental stress (GxE) to disrupt embryogenesis causing heart, vertebral and/or kidney defects

4. Nicotinamide adenine dinucleotide (NAD) deficiency and congenital malformation

We are exploring the role of NAD in mammalian embryogenesis.

We have discovered that:

• NAD deficiency causes multiple congenital malformations in humans through mutation in KYNU, HAAO or NADSYN1.
• NAD deficiency causes multiple congenital malformations and embryo loss (miscarriage) in mice through mutation in Kynu or Haao
• NAD deficiency, congenital malformations and embryo loss (miscarriage) in mice are prevented by vitamin B3 (niacin) supplementation during gestation

• Diet alone can cause NAD deficiency and adverse pregnancy outcomes in wildtype mice