Head and Face Development

Direct visualisation of WNT signalling, shown by the blue staining, in mouse embryos at 7.75 days (left picture) and 9.5 days (right picture) after conception.  Scale bars = 200 µm.







In humans, lethal malformation complexes of the head are associated with varying degrees of anatomical defects of the brain, skull and facial structures.  Congenital malformations of the brain ranging from reduction in size (microcephaly), abnormal partitioning (holoprosencephaly, rhinencephaly) to the severe loss of tissues (anencephaly) has increased to 7.6 per 10,000 births in 2002-3.  In addition, 1.6 per 10,000 births displayed developmental defects of oro-facial structures.  It is believed that these major anatomical defects of the craniofacial structures result primarily from abnormal morphogenesis in the first trimester of human development.  This coincides with the time window of head formation, 7-11 days after conception in the mouse embryo, which is utilized as an experimental model for analysing the genetic and developmental mechanisms of the pathogenesis of the human malformations.

Disorders of development of the head, face and eyes lead to disfiguring malformations in children and require treatment by major corrective surgery.  We are endeavouring to discover the network of genes and molecular pathways involved in head and face development.  Better understanding of these pathways may help in the development of future therapies or preventative measures.

The role of WNT signalling
Intersection of transcriptional and signalling activities
The function of the TWIST1 transcription factor

The role of WNT signalling

The development of the head of the mouse embryo requires a complex interaction of signalling activity of the Bone Morphogenetic Proteins, Fibroblast Growth Factors and WNT ligands.  Loss of function of genes encoding the molecular components of these signalling pathways and the antagonistic factors that modulate the level of signalling activity could lead to dramatic loss of head structures.  We are using several lines of mice that harbour mutations in genes encoding components in the WNT signalling cascade to study the interaction of genes in the formation of the embryonic head.  We have also obtained experimental evidence pointing to an essential role of a specialised midline tissue and the gut endoderm on the patterning of head structures.

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Intersection of transcriptional and signalling activities

We have defined a preliminary network of genetic interactions and our results have revealed a potential link between genes involved in transcriptional regulation and the WNT signalling pathways.  We have also obtained experimental evidence pointing to an essential role of a specialised midline tissue and the gut endoderm on the patterning of head structures.

Specifically, we will utilize genetic and embryological models in which transcription factor coding genes are ablated in a tissue-specific manner to study how their loss in specific types of progenitor cells may impact on the severity of head malformation.  We will also analyze the connection of these transcription factors with WNT signalling activity that, in conjunction, influences tissue differentiation and morphogenetic movement, and elucidate the functional interaction of these transcription factors and WNT signalling in the formation of the embryonic head and face.

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The function of the TWIST1 transcription factor

	Neural crest cells from which much of the skeleton of the jaws, face and skull develops, revealed by a green fluorescent protein reporter in a 10.5 day mouse embryo.

A focus of our research program is the Saethre–Chotzen Syndrome, a disorder of development of the skull, face and limbs which is associated with mutations of the human TWIST1 gene.  The research project is designed to investigate, in the laboratory mouse, the function of the Twist1 gene in a specific population of cells that participate in craniofacial development.  In the mouse, Twist1 gene is active in two cell populations that make up the head: neural crest cells and the mesoderm.  Our research shows that loss of Twist1 function specifically in the neural crest cells leads to a failure to develop the jaws, face and the front and top parts of the skull, whereas loss of gene function in the mesoderm results in the failure to form the back and bottom parts of the skull but not the face or the jaws.

The long-term goal is to construct a network of molecular activity that accomplishes the formation of body parts, and to investigate the role of specific genes in these processes.  A key strategy of our embryological and genetic studies is the generation of mouse models displaying developmental defects that enable us to understand the pathogenesis of human congenital malformations.  Two experimental approaches will be taken for this project:

1. Expression profiling will be performed on the mutant mice to examine the impact of loss of Twist1 function on downstream molecular pathways for the differentiation of cranial neural crest cells.
2. The function of the candidate downstream targets of TWIST1 will be analysed in cell culture models and transgenic mice; and based on the findings, genetic studies will be undertaken through the generation and investigation of mutant mouse models.

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