Left/Right Asymmetry

The visceral organs of the thorax and abdomen develop asymmetrically on the left and right hand sides of the body cavity.  For example, the liver develops predominantly on the right hand side while the spleen, stomach and heart develop to the left.  All organs originate along the midline of the embryo and are subsequently signalled as to which side to develop.  What the signals are and how they are conveyed are the scientific questions that we investigate. 

Projects

1. Analysis of the molecules downstream of Bapx1 responsible for leftward growth of the pancreas and spleen
2. Genetic analysis of the role of RA in left-right asymmetry and of RA signalling in heart, lung and spleen development
3. Development of organ culture systems for analysing in real time the leftward spleen and pancreatic growth at a cellular and tissue level.
   

Relevant Publications

1. Asayesh, A.; Sharpe, J.; Watson, R.P.; Hecksher-Sorensen, J.; Hastie, N.D.; Hill, R.E. and Ahlgren, U. Spleen versus pancreas: strict control of organ interrelationship revealed by analyses of Bapx1-/- mice.
   Genes Dev 20(16):2208-2213, 2006
   PubMed Abstract
   
   
2. Hecksher-Sorensen, J.; Watson, R.P.; Lettice, L.A.; Serup, P.; Eley, L.; De Angelis, C.; Ahlgren, U. and Hill, R.E. The splanchnic mesodermal plate directs spleen and pancreatic laterality, and is regulated by Bapx1/Nkx3.2.
   Development 131:4665-4675, 2004
   PubMed Abstract
   
   
3. Tucker, A.S.; Watson, R.P.; Lettice, L.A.; Yamada, G. and Hill, R.E. Bapx1 regulates patterning in the middle ear: altered regulatory role in the transition from the proximal jaw during vertebrate evolution. Development 131(6):1235-1245, 2004
   PubMed Abstract
   

These fall into two parts:

1. Limb Asymmetry and Long Range Regulation of Shh
2. Left/Right Asymmetry (this page)

Abnormalities in the normal development of laterality lead to discordant left-right placement of the internal organs giving rise to a number of classes of birth defects. 

The most severe are congenital cardiac defects, but commonly organ isomerisms occur.  These include polysplenia, asplenia, and defects in gut looping.  We have identified the homeobox gene, Bapx1, which has localised affects on the 3-dimensional placement of the stomach, spleen and pancreas. 

Bapx1 regulates the signalling from a novel embryonic organiser we have dubbed the SMP (splanchnic mesodermal plate) (shown below).  In collaboration with David Fitzpatrick we are analysing a gene responsible for the Matthew Wood Syndrome which effects heart asymmetry, lung hypoplasia and rudimentary spleen.  This gene is a membrane bound retinoic acid (RA) receptor.

Signaling by the SMP to guide leftward growth of spleen and pancreas