Making and breaking the left-right axis in Cancun

Just before the ISDB meeting in Mexico, over a hundred researchers gathered for a satellite symposium on the development of left-right asymmetry. Although the external body plans of vertebrates (and many invertebrates) are bilaterally symmetrical, various internal organs are positioned asymmetrically. For example, the heart is located towards the left, but paired organs such as the lungs are also asymmetrical, as the left lung has fewer lobes than the right in order to make space for the heart on that side of the body. Correct development of the left-right axis is vital for all organs to be packaged properly within the body cavity, so left-right defects often have disease implications.

The symposium began by looking at left-right patterning in some of our more distant relatives: flies, nematodes, polychaete worms, limpets, sea squirts and sea urchins.

Bill Wood used a nice visualisation to describe left-right asymmetry in the early C. elegans embryo, telling us to imagine the one-cell embryo as a cylinder with the M.C. Escher artwork ‘Bird Fish’ wrapped around it. As the embryo prepares for its first cell division into anterior and posterior cells, there is an off-axis deformation of the cortical network that stretches the birds and fish so that they are longer and thinner on one side of the cylinder. This means that the birds and fish on the other side are pulled in the opposite direction and become shorter and fatter, creating a difference between the future left and right sides of the body during the very first cell division. ‘Bird Fish’ seemed an appropriate choice of pattern to demonstrate this point as the model organisms representing these two groups, chick and zebrafish, use very different mechanisms to establish left-right asymmetry and would be discussed later in the meeting…

We then moved on to vertebrate systems with talks describing the events taking place at the node of mouse and its analogous structures in other animals, where motile cilia generate leftward fluid flow. Dominic Norris proposed a mechanism for the detection of this flow, which initiates a Nodal signal on the left side of the body, while Chris Wright and Jose Antonio Belo talked about the dynamics of Nodal ligands and antagonists, respectively.

A recurrent debate was the role of early determinants of asymmetry, and how these might work with the cilia-mediated mechanism seen in many, but not all vertebrates. Martin Blum proposed a model to accommodate both processes and discussed their possible evolutionary relationships. The frequently mentioned ‘problem’ with a cilia-based strategy is that some animals establish the left-right axis without cilia, such as the chick. Leonor Saude described the asymmetry created by the leftward movement of cells around Hensen’s node and the termination of this process by a cell adhesion mechanism.

The early differences between the left and right sides of the body must be translated into an effect on organogenesis later in development. This was addressed by Rebecca Burdine who showed that the Nodal signal increases cell movement on the left side of the zebrafish heart tube to facilitate its leftward jog, and Nanette Nascone-Yoder who has been investigating the role of the left-specific transcription factor Pitx2 in asymmetric gut curvature in frogs.

Even organs that appear symmetrical in their gross morphology can be asymmetrical; the brain exhibits many functional asymmetries. Steve Wilson has utilised the optical clarity of zebrafish to visualise asymmetric connections in the brain and asymmetric activity in response to stimuli, while Marnie Halpern described some ways in which reversed brain asymmetry can affect fish behaviour.

In contrast to the talks on asymmetry, Olivier Pourquie explained how symmetrical structures such as the somites overcome the differences between the left and right sides of the body to maintain their symmetry during development.

The medical relevance of left-right axis development was summed up by talks on diseases associated with asymmetry defects; Cecilia Lo described her work on congenital heart disease and Zhaoxia Sun spoke about primary ciliary dyskinesia. Research into left-right asymmetry has even inspired a recent article in the New York Times, so a developmental process that has fascinated scientists for decades has infiltrated popular culture too – it must be important!

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