Serial deletions and duplications suggest a mechanism for the collinearity of Hoxd genes in limbs.
Hox genes, located at one end of the HoxD cluster, are essential for the development of the extremities of our limbs; that is, the digits. This 'collinear' correspondence is accompanied by a gradual decrease in the transcriptional efficiency of the genes. To decipher the underlying regulatory mechanisms, and thus to understand better how digits develop, we engineered a series of deletions and duplications in vivo. We find that HoxD genes compete for a remote enhancer that recognizes the locus in a polar fashion, with a preference for the 5' extremity. Modifications in either the number or topography of Hoxd loci induced regulatory reallocations affecting both the number and morphology of digits. These results demonstrate why genes located at the extremity of the cluster are expressed at the distal end of the limbs, following a gradual reduction in transcriptional efficiency, and thus highlight the mechanistic nature of collinearity in limbs.
Kmita
Marie
M
Department of Zoology and Animal Biology, NCCR Frontiers in Genetics, University of Geneva, Sciences III, Quai Ernest Ansermet 30, 1211 Geneva 4, Switzerland.
Fraudeau
Nadine
N
Hérault
Yann
Y
Duboule
Denis
D
D000818:Animals; D005075:Biological Evolution; D004268:DNA-Binding Proteins / Q000235:genetics; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005121:Extremities / Q000196:embryology*; D005260:Female; D017353:Gene Deletion; D020440:Gene Duplication; D015870:Gene Expression / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D005801:Genes, Homeobox / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D008297:Male; D008540:Meiosis; D051379:Mice; D008957:Models, Genetic; D009024:Morphogenesis / Q000235:genetics; D005810:Multigene Family / Q000235:genetics*; D016297:Mutagenesis, Site-Directed; D011995:Recombination, Genetic; D014158:Transcription, Genetic / Q000235:genetics
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C074438:Evx2 protein, mouse