How does encephalocele develop prenatally and can it be prevented by folic acid?

Supervisors: Professor Andrew Copp and Dr Erwin Pauws

This project involves study of a new mouse genetic model of encephalocele in order to:

1. Reveal the pathogenesis of this birth defect, prenatally;
2. Examine whether supplementation with folic acid can prevent encephalocele, as for open neural tube defects.

Encephalocele is a severe birth defect of skull and brain affecting 0.1-0.3 per 1000 established pregnancies [1]. Some brain tissue becomes located outside the skull in a meningeal sac and, despite neurosurgical repair, post-operative health problems are common, including learning difficulties, hydrocephalus and epilepsy. Most cases of encephalocele are sporadic and of unknown causation. While traditionally considered a ‘neural tube defect’ – that is, like anencephaly and open spina bifida – there is no consensus on how encephalocele actually develops prenatally. Moreover, it is unknown whether folic acid, which prevents many cases of spina bifida, can also prevent encephalocele. A careful developmental study in a suitable animal model is needed to reveal the origin and folate-responsiveness of encephalocele, as our team has already done for open neural tube defects [2].

Plan of research:
The student will use a newly developed mouse model of encephalocele, based on genetic recombination of a floxed allele of the Rac1 gene by Grhl3 driving Cre recombinase. The following research questions will be addressed:

1. What is the timing of origin of encephalocele development prenatally? Embryos and fetuses from the Grhl3Cre; Rac1flox mice will be studied at various stages through pregnancy in order to determine whether encephalocele arises at the time of neural tube closure, or is a post-neurulation defect.
2. What is the embryonic pathogenic mechanism leading to brain protrusion? The primary defect in the Grhl3Cre; Rac1flox encephalocele model seems to involve local disruption of the developing epidermis and sub-epidermal tissues. This mechanism will be studied in detail, with a focus on (i) timing of the ‘loss’ of epidermis by histology and immunohistochemistry, and (ii) occurrence of cell death (e.g. apoptosis).
3. Is the frequency of encephalocele dependent on folic acid status? The Grhl3Cre; Rac1flox mouse model will be studied under conditions of dietary folate deficiency, or folate supplementation, to determine whether the frequency or severity of encephalocele is altered.

This study could pave the way towards an improved understanding of sporadic encephalocele. It will also provide a starting point for examining the pathogenesis of encephalocele in Meckel syndrome where the causation and sub-cellular disturbance (ciliopathy), but not pathogenesis, are already known [3]. If FA supplementation is able to reduce the frequency or severity of encephalocele in the model system, this will encourage further studies of the extent to which human encephaloceles may be prevented by FA supplementation and food fortification.

Laboratory environment:
The student will work in a well-funded lab in which several postdoctoral fellows are available to supervise the laboratory work of early-stage students. The research team has regular informal lab meetings & journal clubs to enhance the educational experience of PhD students. For more information, see our web page:

1) Bui C.J., et al (2007). Institutional experience with cranial vault encephaloceles. J. Neurosurg. 107: 22- 25.
2) Copp A.J. and Greene N.D.E. (2010). Genetics and development of neural tube defects. J. Pathol. 220: 217-230.
3) Logan C.V., et al (2010). Molecular genetics and pathogenic mechanisms for the severe ciliopathies: Insights into neurodevelopment and pathogenesis of neural tube defects. Mol. Neurobiol. 43: 12-26.