INTERSPECIES EXCHANGE OF A HOXD ENHANCER IN-VIVO INDUCES PREMATURE TRANSCRIPTION AND ANTERIOR SHIFT OF THE SACRUM

The precise activation, in space and time, of vertebrate Hox genes is an essential requirement for normal morphogenesis. In order to assess for the functional potential of evolutionary conserved Hox regulatory sequences, a phylogenetically conserved bipartite regulatory element n ecessary for proper spatial and temporal activation of the Hoxd-11 gen e was replaced by its fish counterpart in the HoxD complex of mice, us ing an ES cell-based targeted exchange. Fetuses carrying this replacem ent activated Hoxd-11 transcription prematurely, which led to a rostra l shift of its expression boundary and a consequent anterior transposi tion of the sacrum. These results demonstrate the high phylogenetic co nservation of regulatory mechanisms acting over vertebrate Hox complex es and suggest that minor time difference (heterochronies) in Hox gene activation may have contributed to important morphological variations in the course of evolution. (C) 1997 Academic Press.