A few brief days in embryonic life lays out our body's construction plan. The appearance of limbs and vertebrae is orchestrated by a family of 'architect' genes called Hox, each providing precise instructions at a given time.
New research has demonstrated that these genes were aligned within our chromosomes according to the order of structures - collinear expression in developing limb buds: first the components of the shoulder, then the arm, and finally the fingers.
The cluster of Hoxd genes coordinates the operations of limb formation, in particular. These genes are transcribed in two successive waves, allowing the development of the arm, then the hand.
"We had already discovered that the genes responsible for the hand were controlled by enhancers, specific DNA sequences located in an adjacent area, at one end of the Hoxd cluster. This regulatory domain takes on a different three-dimensional configuration, according to the degree of activity of the enhancers," says Professor Denis Duboule, a geneticist at the Faculty of Science of the University of Geneva (UNIGE) and at the Swiss Federal Institute of Technology in Lausanne (EPFL).
Two distinct regulatory domains
In order to understand the molecular processes that preside over arm formation, as well as the transition to wrist and hand formation, the researchers used sophisticated techniques of genetic engineering, molecular biology, and murine embryo cell lines. "Curiously, certain Hoxd genes are involved in the origin of both the arm and the hand, while it is their absence of expression that enables wrist formation," notes Guillaume Andrey, former doctoral student at the Frontiers in Genetics National Research Center and first author of the article.
The biologists demonstrated the existence of a second regulatory domain.
However, there is an intermediary cellular territory that escapes the two regulatory controls and in which the switch is not activated: this zone will generate the wrist.
However, it is responsible for arm development and is located at the other end of the Hoxd gene cluster. They decrypted the complex dialogue established between these genes and the two adjacent domains: "Certain Hoxd genes associate with only one of the two domains, whereas others interact with both, but in different cells and at separate times," explains Guillaume Andrey.
The wrist emerges from a no man's land
During the growth of the limb bud, certain Hoxd genes will shift toward the opposite regulatory domain to establish new contacts. This swing from one domain to the other is the equivalent of a genetic switch, signaling the transition between the creation of the arm and the hand. However, there is an intermediary cellular territory that escapes the two regulatory controls and in which the switch is not activated: this zone will generate the wrist. Thus, the articulation of activities between domains A and B enables the appearance of a mor- phological articulation between our arms and our hands.
"The three-dimensional organization of these two regulatory domains, which gives them physical and functional independence, plays an essential role in stimulating the Hoxd genes. These experiments allowed us to demonstrate that there is an additional, topological level of information to modulate gene expression. This is a first!"' says Guillaume Andrey.