A dual role for Hox genes in limb anterior-posterior asymmetry.
Anterior-to-posterior patterning, the process whereby our digits are differently shaped, is a key aspect of limb development. It depends on the localized expression in posterior limb bud of Sonic hedgehog (Shh) and the morphogenetic potential of its diffusing product. By using an inversion of and a large deficiency in the mouse HoxD cluster, we found that a perturbation in the early collinear expression of Hoxd11, Hoxd12, and Hoxd13 in limb buds led to a loss of asymmetry. Ectopic Hox gene expression triggered abnormal Shh transcription, which in turn induced symmetrical expression of Hox genes in digits, thereby generating double posterior limbs. We conclude that early posterior restriction of Hox gene products sets up an anterior-posterior prepattern, which determines the localized activation of Shh. This signal is subsequently translated into digit morphological asymmetry by promoting the late expression of Hoxd genes, two collinear processes relying on opposite genomic topographies, upstream and downstream Shh signaling.
Zákány
József
J
Department of Zoology and Animal Biology and National Program Frontiers in Genetics, University of Geneva, Sciences III, Quai Ernest Ansermet 30, 1211 Geneva 4, Switzerland.
Kmita
Marie
M
Duboule
Denis
D
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D019521:Body Patterning; D007446:Chromosome Inversion; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005552:Forelimb / Q000002:abnormalities / Q000196:embryology*; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting; D005801:Genes, Homeobox; D053823:Hedgehog Proteins; D006579:Heterozygote; D006614:Hindlimb / Q000002:abnormalities / Q000196:embryology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006720:Homozygote; D051741:Kruppel-Like Transcription Factors; D018878:Limb Buds / Q000196:embryology* / Q000378:metabolism; D051379:Mice; D009024:Morphogenesis; D009419:Nerve Tissue Proteins; D011995:Recombination, Genetic; D015398:Signal Transduction; D014034:Toes / Q000002:abnormalities / Q000196:embryology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D029961:Zebrafish Proteins; D000074290:Zinc Finger Protein Gli3
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D029961:Zebrafish Proteins; D000074290:Zinc Finger Protein Gli3; C465571:Gli3 protein, mouse; C498766:Hand2 protein, mouse; C490939:Hoxd11 protein, mouse; C490943:Hoxd12 protein, mouse; C084118:Hoxd13 protein, mouse; C410915:hand2 protein, zebrafish