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Development

A Gene to Orchestrate Organ Distribution

CNRS researchers have identified a gene fundamental for the establishment of right/left asymmetry in fruit flies. This discovery could shed more light on the development of human malformations and diseases associated with left-right asymmetry defects.

To a certain extent, both right and left sides of our external bodies are symmetrical. On the inside, however, many visceral organs are either displaced to one side (the heart), form a loop in a particular direction (the gut), or, if they are bilateral, present different morphologies on the right and on the left (the lungs).

In all vertebrates and invertebrates, the development of the embryo begins symmetrically. Very early on, however, a phenomenon called “symmetry breaking” occurs, which leads to the appearance of an internal right/left axis, according to which asymmetric organs place themselves across the midline.

Defects in the establishment of the right/left axis can trigger developmental abnormalities. An estimated 1 in 5000 to 10,000 individuals are impaired by disorders linked to right/left asymmetric defects, such as congenital heart failure, biliary tract anomalies, and polycystic kidney disease. Right/left asymmetry defects are also often the cause of natural abortion.

While considerable effort has been made over the last decades to understand the molecular and genetic mechanisms underlying the establishment of the two other axes of embryonic development–the anteroposterior and the dorsoventral axes–very little is known about the right/left asymmetry process, especially among invertebrates.

In vertebrates, a few asymmetrically-expressed genes have been discovered. The Nodal gene, for example, is expressed solely on the left. First identified among chick embryos, it has since been found in every studied vertebrate, including frogs, fish, and mice. Speculations have also been put forward as to how symmetry breaking might occur in vertebrates.

“In vertebrates, symmetry breaking has been thoroughly investigated, and hypotheses that have been put forward–in particular the 'nodal flow' model–are now supported by strong data,” says Dr. Stephane Noselli, from CNRS's Institute of Signaling, Developmental Biology & Cancer in Nice.1 “But understanding how this process occurs among invertebrates and non-mammalian vertebrates is still a mystery.”

 

Recently, however, Noselli's team discovered a determinant gene for symmetry breaking in fruit flies. In two separate studies recently published in Nature,2 the researchers identify situs inversus fruit fly mutants–that is, mutants presenting a complete reversal of right/left asymmetry. Such mutants are rare in nature, as only one had so far been identified in the mouse and the snail.

“These mutants are the key to identifying mechanisms controlling asymmetry,” says Noselli. “When you are dealing with a situs inversus, it strongly suggests that the affected gene is one that participates in the decision of what goes on the left and what goes on the right.”

In one of the studies, the researchers looked at the reverse coiling of the genitalia–a left-hand spiral rather than the wild type right-hand coil–of the situs inversus mutants. In the second study, they focused on the flies' intestines. “These two features are two strong markers of right/left asymmetry inside the fly,” says Noselli. “Our studies have shown that it is the same gene that is affected, and we can generalize that this one gene is implicated in the control of asymmetry inside Drosophila.”

This determinant gene, called Myo31DF, which belongs to the unconventional Myosin ID family, codes for a protein with molecular motor activity. In the embryo, this gene is expressed both on the left and on the right sides, which indicates that this expression occurs before symmetry breaking takes place. “This is what you would expect from a determinant,” explains Noselli. “Although theoretically expected,” says Noselli “it is the first time an element of the myosin family is involved in establishing right/left asymmetry.”

Highly conserved homologues of this myosin can also be found in humans, yet there is no evidence to suggest that the gene might be involved in asymmetry in vertebrates. “It could either be conserved throughout the animal kingdom, specific to invertebrates, or even solely to Drosophila,” adds Noselli.

 

Clémentine Wallace 

Notes :

1. Institut de signalisation, biologie du développement et cancer (CNRS / Université Nice joint lab). www.unice.fr/isdbc/1.
2. Both studies are published in the April 6, 2006, issue of Nature.
P. Spéder et al., “Type ID unconventional myosin controls left-right asymmetry in Drosophila,” Nature. 440 (7085): 803-7. 2006.
S. Hozumi et al., “An unconventional myosin in Drosophila reverses the default handedness in visceral organs,” Nature. 440 (7085): 798-802. 2006.

Contacts :

Stéphane Noselli
Noselli@unice.fr


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