Heart disease, Primary Ciliary Dyskinesias, Left-Right patterning, cilia, development

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While externally mirror symmetrical between left and right the mammalian body shows left-right (L-R) asymmetry in the placement and patterning of organs and vasculature. While complete inversion of sidedness (situs inversus) is viable, incomplete conversions (situs ambiguous) carry serious health implications. The humans conditions polyasplenia, primary ciliary diskinesias (PCD) and Kartagener syndrome, cause situs inversus and situs ambiguous. A significant level of congenital heart disease (CHD) is associated with these defects and it has become obvious in recent years that CHD can be the sole manifestation of low level L-R patterning defects. Situs defects are also associated with extrahepatic biliary atresia and polycystic kidney disease; these too are associated with CHD. Understanding the genetics of L-R development will therefore aid understanding of not merely situs defects but of CHD, PCD and cystic kidney disease.
During mammalian development, L-R symmetry is thought to be broken at the embryonic node when motile cilia create a leftward flow of liquid. Although models to explain this have emerged, it remains unclear how the flow is perceived by the developing embryo. Positional information is then communicated, by an unknown mechanism, from the node to the left lateral plate, activating Nodal which in turn activates Pitx2 expression. However, Pitx2 null embryos do not loose all aspects of left sidedness, making it clear that additional uncharacterised signals distinguishing the left and right sides of the embryo.
We have identified a gene novel to L-R determination, expressed in the left lateral plate and on the right side of the node. Preliminary data suggests its expression is independent of Nodal and Pitx2. It is possible that this gene may be responsible for aspects of leftness still present in Pitx2 null embryos. We aim to investigate both the function and control of this gene.
We have identified 11 mutants affecting L-R determination; seven appear novel. We will characterise the events occurring as these mutants attempt to establish L-R asymmetry, with particular attention on events at the node. We will refine map positions for these mutants and identify the genes mutated. We will integrate this information with existing models of L-R development and with the network of genes controlling L-R development. We will refine, develop and test models emerging from our results. Further, through collaboration, we will screen cardiac patients for defects in the genes implicated by this work.