Dr Seb Dworkin on his scientific ‘fishing
expedition’ with zebrafish embryos,
teasing out the genetic origin of cranio-
The alternative is to prevent the defect from occurring in the first place, which means its cause must be understood. The problem stems from an error in the genetic instructions for the facial formation. However, which genes? Which sequences? What affects the genes? There are hundreds of possible causes, and without knowing exactly which genes are involved in the process of embryo formation, it will not be possible to develop preventive gene therapies.
Dr Seb Dworkin is a Senior Research Officer in the Epidermal Development Laboratory headed by Professor Stephen Jane. He is working on identifying the specific gene sequence errors which result in craniofacial deformity. In 2013 Dr Dworkin was awarded both a National Health and Medical Research Council (NHMRC) grant and an ARC Discovery Early Career Researcher Award (DECRA) for his research.
An ancient gene family, called the Grainy head-like (Grhl) genes, spanning over 750 million years of evolution are conserved in diverse organisms, from flies to humans. Previous research has shown that the Grhl genes regulate many functions, including skin development, wound healing and neural tube closure, which was Dr Dworkin’s first area of investigation. His research is now showing the gene family’s role in facial bone formation. One gene, Grhl2 is responsible for facial skeleton development and another, Grhl3, regulates multiple stages of embryonic formation. These genes play a similar role in fly, frog, zebrafish and mouse, and using these animal models can help researchers understand the genetic causes of human disease.
The DECRA funded project is using the zebrafish model to investigate the role played by grhl3 in embryonic development. This project is characterising the role of grhl3 in the regulation of cellular migration,craniofacial skeleton and brain development. The project also aims to identify the target genes which Grhl3 regulates. The identification of the networks controlling the genetic flow of information is essential to understanding genetic control of embryogenesis and development.
The NHMRC funded project is looking at upper and lower jaw development in a mouse model, because the mechanism of jaw formation is similar to humans. It will also entail analysis of human tissue from cleft palate and facial defect patients to identify if they have similar genetic defects to those observed in the animal models.
The projects involve interdisciplinary collaboration with local (Walter & Eliza Hall Institute stem cell and developmental biologists), national (craniofacial surgeons) and international (US and German cleft palate and facial deformity) researchers.
Dr Dworkin says, “It’s of great benefit for our research projects to have a variety of species showing that the same mechanism is involved in each. It makes it that much more likely that whatever we discover will be applicable for human therapies.”