Interspecies Exchange of a Hoxd Enhancer in Vivo Induces Premature Transcription and Anterior Shift of the Sacrum

AbstractThe precise activation, in space and time, of vertebrateHoxgenes is an essential requirement for normal morphogenesis. In order to assess for the functional potential of evolutionary conservedHoxregulatory sequences, a phylogenetically conserved bipartite regulatory element necessary for proper spatial and temporal activation of theHoxd-11gene was replaced by its fish counterpart in theHoxDcomplex of mice, using an ES cell-based targeted exchange. Fetuses carrying this replacement activatedHoxd-11transcription prematurely, which led to a rostral shift of its expression boundary and a consequent anterior transposition of the sacrum. These results demonstrate the high phylogenetic conservation of regulatory mechanisms acting over vertebrateHoxcomplexes and suggest that minor time difference (heterochronies) inHoxgene activation may have contributed to important morphological variations in the course of evolution