A step towards unraveling the genetic pathways of left-right body asymmetry

Researchers at the Instituto Gulbenkian de Ciência (IGC), in Portugal, have taken a major step forward in understanding one of the fundamental questions in the field of developmental biology today: how the organs are placed in their correct positions in the body. In a study published in the 1st October issue of the journal Genes and Development, the scientists describe, for the first time, the role of the gene Cerl-2 (Cerberus-like-2), in setting up the asymmetric distribution of organs in the embryo, that is, why the heart always is always on the left and the liver always on the right hand side of the body, for example.

The team of scientists, lead by José António Belo, made genetically altered mice, in which the Cerl-2 gene is not functional, known as ‘knockout’ mice. These animals show several physical changes, such as lungs with two identical lobes (the left lobe), left-right inversions of the heart and lungs and of some abdominal organs (the stomach, the duodenum and the kidneys, for example).

The effect of Cerl-2 on the left-right asymmetry of the embryos seems to be a result of its role as an antagonist of another gene previously implicated in this process, known as Nodal. Nodal is switched on asymmetrically in the embryo, only on the left hand side of a tissue called the lateral plate mesoderm (there is also the right lateral plate mesoderm) and in the left half of the node (a signaling structure that is crucial for the correct development of the embryo). Nodal turns on a signaling cascade of genes, restricted to the left hand-side of the embryo. On the other hand, Cerl-2 is switched on in only the right half of the node, adjacent to the area of Nodal.

The IGC scientists have also shown, for the first time, that, when Cerl-2 is absent, Nodal is switched on in the right lateral plate mesoderm too, or even only on this side. As a result, the chain of reactions triggered by Nodal becomes active on both sides and the embryo no longer knows which is left and which is right leading to the incorrect organ distribution seen in the ‘knockout’ mice.

Many research groups, all over the world, are looking into the mechanism, or mechanisms, that break the early symmetry of the embryo, thus creating asymmetric organisms. Cilia (short tail-like structures) on the node cells have recently been described as playing a role in symmetry breaking: their leftward rotation guides the asymmetric switching on of genes and later organ distribution. According to José António Belo, their study now demonstrates that another genetic mechanism is acting in parallel with the cilia: it all takes place in the node, soon after the embryo is formed, and involves Cerl-2 controlling the asymmetric activity of Nodal.

This study is the latest of a series published in several leading scientific journals, during the five years of setting up and running the group. The team shall be moving to the University of the Algarve, in the south of Portugal, where José António Belo is Assistant Professor.

According to António Coutinho, Director of the IGC, this study is yet a further example of the patent success of the IGC in its mission to give young scientists the opportunity to install their teams, over a five-year period, before moving on to universities and other research centres in the country. During the five years spent at the IGC, the team leaders develop and establish themselves within the scientific community, so that the move to other centres may be smooth and problem-free for all: the scientists themselves, the universities and the IGC, that remains open to host other young scientists.