Analysing the cellular basis of palate morphogenesis and clefting

Cleft lip and cleft palate are common birth defects that can seriously affect facial appearance and oro-facial function, including the development of speech and language, feeding and nutrition, whilst negatively impacting on general physical and mental health and life expectancy. They represent a failure of certain parts of the face and roof of the mouth to form correctly and can result in significant tissue defects in the face and mouths of babies when they are born.

Although surgical correction of these defects is possible to some extent, multiple and repeated surgeries during infancy and childhood are often required and these rarely provide complete restoration of normal appearance or function. People affected by cleft lip and palate are therefore often afflicted by very obvious facial scarring for their whole life, coupled with frequent speech problems and a defective bite.

As a result of these issues, they can find social integration difficult and often struggle to achieve their full potential in life. Cleft palate can leave an open communication between the mouth and nose, making eating and drinking difficult and socially embarrassing.

Cleft lip and palate occur because of a failure during normal development of the face early in pregnancy. We know quite a lot about the genetic basis of this condition, but hardly anything about how disrupted function of different genes influences cells in the embryo and how they behave during development of the lip and palate. It would be much better to use knowledge of the biology of what cells are doing in the embryo to repair and regenerate the relevant tissues as the baby develops, rather than allowing the defect to occur and then attempting correction with surgery.

This goal may not be as far out of reach as you might imagine but does require a much better understanding of how cells make the face and palate in the first place.

This project will investigate how cells multiply, move and change shape during development of the palate, ensuring that this structure is continuous in the roof of the mouth when a baby is born and able to seal off the mouth from the nose. This will be done using laboratory mice because the palate forms in a very similar way in the mouse embryo when compared to the human.

Special mice will be bred that have been genetically modified to have particular cells labelled fluorescently. This fluorescence can be switched on by giving the mouse certain drugs - so we can control exactly when and where the labelled cells become fluorescent in the palate. This will allow us to watch exactly how these cells multiply and move during development of the palate because they can be tracked in detail under the microscope.

Normal mice will be compared to mice strains that have cleft palate so that the different ways that cells behave when a cleft palate develops can be understood in terms of which cells are not doing the right things in the right places. We can do this through all stages of development of the palate. We will be applying and developing new ways of using image analysis and computer processing to describe the different movements, shape changes, cell directions and cell multiplications that occur during normal development of the palate and when things go wrong in cleft palate.

This will provide a deeper, higher-resolution understanding of how the palate and face are made during development and how cleft palate happens. This type of research project means that one day we may be able to use this knowledge to reconstruct, regenerate and repair tissues in the embryo through redirecting cells and therefore, avoid surgical correction with all of its current limitations.

In addition, the information generated by this project will also be of use to other scientists who study embryonic development and growth of other tissues in the body. It is only by understanding what cells do during normal development that we will learn how to correct things when they go wrong.