How do our organs know their right from their left?

The heart tilts to the left, the liver occupies the right, the intestines always coil in the same direction, and the two lungs have neither the same shape nor the same number of lobes. This internal organization, invisible from the outside, is established in the very first days of the embryo, and the heart depends on it to maintain its dual blood circulation.

When it fails, the child is born with a rare disease, heterotaxy: the organs each orient to their own side, no longer coordinated with one another. The syndrome affects approximately one in 10,000 births and, in the vast majority of cases, is accompanied by severe heart malformations. It is these, rather than the position of the organs, that put the child’s life at risk. Today, a genetic cause is identified in only one patient in five.

In a study published in Science Advances, Sigolène Meilhac’s team (Inserm, Institut Imagine, Institut Pasteur, Université Paris Cité) shows, in a mouse model, that the mechanism long considered the founding event of left-right asymmetry—the ciliary flow—is not its generator: it merely orients it. A second mechanism, until now unsuspected and involving one of the major pathways of communication between cells during development, the WNT pathway, complements it.

For thirty years, a fluid flow was thought to be the origin of asymmetry

Since the late 1990s, embryology has agreed on a mechanism: at a very early stage of development, a small cup-shaped cavity, called the node, houses cilia that, rotating on themselves, move the surrounding fluid to the left. This flow triggers a molecular cascade, dominated by the Nodal gene, which then defines the left side of the embryo. The node was even named the “left-right organizer,” according to a simple principle: no flow, no asymmetry.

To test this model, the researchers worked with mice carrying a mutation in the Ccdc40 gene, which paralyzes the cilia. In humans, this gene is the third most frequently implicated in primary ciliary dyskinesia, a rare disease combining chronic respiratory disorders, infertility and, in some patients, organs arranged in a mirror image of normal.

They first verified, in the mice, that the flow had indeed disappeared. Under the electron microscope, the cilia appeared deformed. By filming fluorescent microbeads placed in the node, no fluid movement was detected. The abolition was complete in all the animals studied.

Once the flow was cut off, the expected disorder did not occur

By reconstructing in three dimensions, organ by organ, the anatomy of the newborn mice, the team expected disorder. It observed the opposite.

In 70% of the animals, the organs were perfectly well placed. Among the remaining 30%, half of the animals had all their organs in a mirror-image position, a configuration called situs inversus totalis, most often without clinical consequences. The other half had developed heterotaxy and heart malformations. These proportions are not due to chance: without any flow, the embryo continues to produce asymmetry. It simply no longer always knows which direction to turn it.

“The flow is not the engine of asymmetry; it is a switch,” explains Sigolène Meilhac, Inserm research director, team leader at the Institut Imagine and the Institut Pasteur, and last author of the study. “It orients a mechanism that already exists but is not very robust. Its role is to make the outcome reliable, not to create it.”

The WNT pathway, a second conductor

To identify this other mechanism, the researchers compared, within the same embryo, gene activity on the left and right sides of the future heart. Three developmental trajectories emerged, corresponding exactly to the three outcomes observed at birth: normal asymmetry, a complete mirror image, or a disorganized arrangement.

The signal came not only from the pathway dominated by the Nodal gene, as expected, but also from another: the WNT pathway, one of the major pathways of communication between cells during development. By artificially activating it in embryos cultured in the laboratory, the team was able to disrupt their asymmetry, showing that this second pathway is not merely a marker, but indeed an actor.

Why the heart and lungs are affected together

This lead led to an unexpected discovery. The researchers identified a group of cells that no one had ever suspected of being asymmetric as well: those that build both the heart and the lungs.

This may explain a well-known clinical observation that had remained unanswered: in heterotaxy, heart abnormalities and lung abnormalities almost always go together.

Toward a better understanding of heterotaxy

This work answers a question geneticists have long asked: why do two patients carrying the same genetic mutation, sometimes within the same family, present such different clinical pictures—from complete organ reversal, with no symptoms, to severe heart disease?

By describing the three possible trajectories and the anatomical and molecular landmarks that distinguish them, the study paves the way for better stratification of these malformations. It also invites researchers to broaden the search for genetic causes to genes that research has not explored until now.

Source

Wnt and Nodal asymmetries stratify mouse laterality phenotypes in the absence of node flow. Science Advances, 2026.
DOI: 10.1126/sciadv.adx6486

Work carried out within the Heart Morphogenesis Unit (Institut Imagine – Institut Pasteur, Inserm UMR1163, Université Paris Cité), under the direction of Sigolène Meilhac, with Amaia Ochandorena-Saa as first author.

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