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A System Approach to Hox Genes Regulation in Vertebrates

Final Report Summary - SYSTEMSHOX.CH (A System Approach to Hox Genes Regulation in Vertebrates)

This ERC project aimed at understanding how the Hox gene family, also called the ‘architect genes’, are controlled during mammalian development. In other words, how are these genes properly activated at the right time in the right cells and tissues? What is the chain of controls leading to their coordinated activation? This question is critical as mistakes in this process immediately generates morphological problems associated with the general construction of the organisms, such as for example an additional vertebra, abnormal digits or defects in the uro-genital system, all conditions quite frequent in human newborns. In addition, we wanted to understand how these genes have evolved and how their controls have been adapted along with the evolution of vertebrates. For instance, why do birds have 14 cervical vertebrae while we only have seven? Why and how do birds have wings and we have arms? In all these cases, the behaviors of these Hox genes have been modified and we would like to understand the intimate nature of these modifications.
We used the laboratory mouse as a model system, because it allowed us to engineer various chromosomes and see the impact on the development of the animals. In this way, we have uncovered a mechanism whereby the group of genes is originally organized in a closed configuration, tightly packed. At the time of their activation, genes are progressively taken out of this closed domain and are switched on one after the other, together with the progression of fetal development. This mechanism prevents the terminal genes to be activated at the time the anterior part of the body is being formed. It also makes it sure that the various genes will be activated following the proper sequence, such that the structure of the species will be always respected. For example cervical vertebrae will always be produced before lumbar vertebrae.
These genes also organize various structures of our body (besides the vertebral column), as exemplified by our arms and legs and this is the second question we addressed in the context of this ERC grant. We found that most of the necessary control DNA sequences are located within two gene deserts flanking this small group of genes. Therefore, what was previously referred to as ‘junk DNA’ (long pieces of DNA without genes) in this case contain critical regulatory regions. We have modified these regions genetically and found that the newborn mice have defects in the limbs, which are similar to those seen in human patients with interruptions in the same two gene deserts, for example via a translocation or an inversion.
This current understanding of the regulation of these Hox genes also help understand how novel controls have evolved during the recent history of vertebrates. For instance, how was achieved the morphological transition between the pectoral fin of an ancestral fish and our arms? This evolutionary aspect is the third question we addressed, i.e. which modifications in the regulation of these genes was necessary to promote or accompany major modifications in the vertebrate body plan? We used a comparative approach between species that have large differences in their internal organization. For example, we observed that the expression of Hox genes was dramatically different in the embryos of mice and snakes, which may explain both why snakes have such elongated bodies and why they have lost their limbs. We have now to understand what caused these differences in gene regulation and, most importantly, whether or not such variations were causal in the emergence of novel forms of animals.