A diaphanous control during embryo formation

Apr 9 2008

A gene called Diaphanous (or Dia) has just been uncovered as a major regulator during embryo formation. The research now published in the journal Development shows how Dia mutations in fruit flies embryos result in a serious of defects during morphogenesis (process by which cells differentiate into tissues and structures), including loss of adhesion, abnormal movements and even migration of cells from one tissue to another.

The discovery contributes to a better understanding of how tissue and organ formation is regulated and, consequently, to, one day, be able to intervene therapeutically. Furthermore, the loss of adhesion and abnormal mobility that occurs when Dia is mutated is very similar to what happens during cancer metastases formation, suggesting that this gene might also have a role in cancer.

During morphogenesis the cells change shape and migrate to new positions in order to achieve the right body plan. The cytoskeleton and the adherent junctions are two major structures involved in these processes: while the first is the cell internal scaffolding - a dynamic structure that helps maintaining the cell shape while also mediating its movements - adherent junctions are connections between cell membranes and cytoskeleton elements that maintain adjacent cells together. During morphogenesis, both structures are tightly coordinated in order to achieve the right balance between stability within the tissue and capability to respond to the environmental through shape and motility variations, but exactly how this occurs and which genes/proteins are involved is still far from being understood.

Diaphanous-related formins (DRF) are a class of regulators known to affect events during morphogenesis although their exact mechanism of action has remained unclear due to several experimental problems. In fact, not only most species have more than one DRF with overlapping functions creating difficulties when trying to find “which one does what”, but also DRF mutations tend to kill the mutated cells making experiments unfeasible.

But in the research now published Catarina Homem, a Portuguese PHD student, and supervisor Mark Peifer at the University of North Carolina at Chapel Hill, USA manage to overcome these problems by working in fruit flies (Drosophila) – which have just one DRF – Dia – and by using a temperature-sensitive Dia mutation , which allowed the researchers to reduce the gene expression only after the cells were fully formed – so not compromising their viability - but before their destiny in the tissues was decided. Together with this mutant Homem and Peifer also used Drosophilas with a Dia constitutive mutation – so where the gene is activated all the time instead of the normal on-off switch in accordance with necessity – as well as offspring obtained from crossing the different mutant Drosophila.

By analysing and comparing embryonic tissue formation in the various fruit flies Homem and Peifer were able to discover that Dia stabilises adherent junctions and controls cell movements during morphogenesis, and that this was mediated by affecting the quantity and activation levels of two major proteins involved in cytoskeleton movement and cell-cell adhesion - actin and myosin. Actin and myosin are better known for their role generating muscles’ contractions but actin – which is an integrant part of the cytoskeleton – also reacts with myosin to create the cell membrane tensions that allow the cell to move. Dia mutations were shown to result in several morphogenic defects, including loss of cell adhesion, abnormal motility and even invasion of neighboring tissues.

In conclusion, Homem and Peifer ‘s work reveals Dia as a major regulator molecule for cell adhesion and cytoskeleton function, acting directly on actin and myosin to regulate cell shape, adhesion and movement. Their study is particularly interesting because it uses several mutations and tests them in a variety of tissues creating a full image of Dia’s role in morphogenesis.

Also interesting is the observation that Dia mutations can transform adherent immobile cells into mobile invasive cell that spread into other tissues, a process known to occur when cancer metastases are formed and when cells from the original tumour gain abnormal mobility and migrate spreading the disease to remote locations. It will be interesting now to investigate if it is in fact possible to associate Dia mutations with cancer, something that Peifer’s laboratory – with a strong interest in cancer research – will no doubt do soon.