Regulation of Tbx3 expression by anteroposterior signalling in vertebrate limb development.
Tbx3, a T-box gene family member related to the Drosophila gene optomotor blind (omb) and encoding a transcription factor, is expressed in anterior and posterior stripes in developing chick limb buds. Tbx3 haploinsufficiency has been linked with the human condition ulnar-mammary syndrome, in which predominantly posterior defects occur in the upper limb. Omb is expressed in Drosophila wing development in response to a signalling cascade involving Hedgehog and Dpp. Homologous vertebrate signals Sonic hedgehog (Shh) and bone morphogenetic protein 2 (Bmp2) are associated in chick limbs with signalling of the polarising region which controls anteroposterior pattern. Here we carried out tissue transplantations, grafted beads soaked in Shh, Bmps, and Noggin in chick limb buds, and analysed Tbx3 expression. We also investigated Tbx3 expression in limb buds of chicken and mouse mutants and retinoid-deficient quail in which anteroposterior patterning is abnormal. We show that Tbx3 expression in anterior and posterior stripes is regulated differently. Posterior Tbx3 expression is stable and depends on the signalling cascade centred on the polarising region involving Shh and Bmps, while anterior Tbx3 expression is labile and depends on the balance between positive Bmp signals, produced anteriorly, and negative Shh signals, produced posteriorly. Our results are consistent with the idea that posterior Tbx3 expression is involved in specifying digit pattern and thus provides an explanation for the posterior defects in human patients. Anterior Tbx3 expression appears to be related to the width of limb bud, which determines digit number.
Tümpel
Stefan
S
Division of Cell and Developmental Biology, The Wellcome Trust Biocentre, University of Dundee, Dundee DD1 5EH, United Kingdom.
Sanz-Ezquerro
Juan J
JJ
Isaac
Alison
A
Eblaghie
Maxwell C
MC
Dobson
Julia
J
Tickle
Cheryll
C
D000818:Animals; D019521:Body Patterning; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology; D002352:Carrier Proteins; D002642:Chick Embryo; D005121:Extremities / Q000196:embryology* / Q000637:transplantation; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D053823:Hedgehog Proteins; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009154:Mutation; D011506:Proteins / Q000494:pharmacology; D011784:Quail; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D015534:Trans-Activators / Q000494:pharmacology; D016212:Transforming Growth Factor beta; D016042:Transplantation, Heterotopic; D000099176:Noggin Protein
D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D053823:Hedgehog Proteins; D011506:Proteins; D020825:T-Box Domain Proteins; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D000099176:Noggin Protein; C525718:BMP2 protein, human; C525719:Bmp2 protein, mouse; C509239:SHH protein, human; C106884:TBX3 protein, human; C491460:Tbx3 protein, mouse