Puzzles solved at multiple degrees
Scientists decipher molecular mechanism of formationRead out
One hand has five fingers - usually anyway. But sometimes there are six or more fingers. Individual fingers can grow together again after their formation, doctors speak in these cases of synpolydactyls. Researchers have now succeeded in elucidating the molecular mechanisms involved in the formation of this phenomenon.
In the journal "Journal of Clinical Investigation", the scientists around Stefan Mundlos from the Max Planck Institute for Molecular Genetics and the Charité - Universitätsmedizin Berlin describe that the additional fingers are caused by uncontrolled cartilage formation due to a lack of retinoic acid in the respective Regions of the limb bud is caused.
Hox genes in the sights
It has long been known that synpolydactyly is triggered by a mutation of the so-called Hoxd13 gene. Hox genes are a highly conserved group of genes responsible for the control of other, downstream genes. During embryonic development, they play an important role in the attachment of various body axes and extremities. The Hoxd13 gene normally has a region in which the sequence for the amino acid alanine occurs 15 times in succession. In patients with synpolydactyly, this series is extended by at least seven additional alanines.
The higher the number of repeated alanines, the more severe the malformation becomes. The inheritance of synpolydactyly is dominant, ie, it is sufficient for the development, if only one copy of the gene - of mother or father - is changed. However, the clinical picture becomes even more severe if both parents carry the mutated gene.
How do extra fingers come from?
The aim of the scientists was now to elucidate the mechanisms that lead to the formation of the surplus fingers and the subsequent coalescence. To do so, the researchers studied mice that have six or more fingers due to a gene change. The gene modification of the animals corresponded to the change of the human genome in synpolydactyly. display
The scientists were able to show that two different mechanisms are responsible for the development of the disease. On the one hand, Hoxd13 activates the enzyme Raldh2, which converts vitamin A to retinoic acid in the area of the later hand. Retinoic acid prevents interproximal embryonic cells from turning into cartilage cells.
In contrast, in the areas in which the fingers arise, no Hoxd13 and thus no retinoic acid. Accordingly, cartilage cells can form here, which in the course of further development become fingers. The altered Hoxd13 is significantly less effective than the normal form. As a result, too little retinal acid develops in the area of the later hand, correspondingly more precursor cells change into cartilage cells and the number of fingers increases.
Duplication or new formation?
In addition, the altered form of Hoxd13 also signals to the precursor cells themselves that they are to become cartilage cells. This further enhances cartilage formation in the wrong place. In order to remedy the lack of retins ure, the researchers administered suspicious mice with the appropriate gene modification retins ure. As a result, offspring were born, who again had the normal number of five fingers.
"Previously, scientists assumed that the formation of additional fingers by duplication of existing finger systems arises, so already existing fingers are duplicated, " explains Mundlos. However, we have been able to prove that the synpolydactyls are formed by differentiation defects. This means that completely new fingers are formed, which do not correspond to any of the normally occurring fingers.
(idw - Max Planck Institute for Molecular Genetics, 17.12.2008 - DLO)