title: Timed deletion of Twist1 in the limb bud reveals age-specific impacts on autopod and zeugopod patterning.
abstract: Twist1 encodes a transcription factor that plays a vital role in limb development. We have used a tamoxifen-inducible Cre transgene, Ubc-CreERT2, to generate time-specific deletions of Twist1 by inducing Cre activity in mouse embryos at different ages from embryonic (E) day 9.5 onwards. A novel forelimb phenotype of supernumerary pre-axial digits and enlargement or partial duplication of the distal radius was observed when Cre activity was induced at E9.5. Gene expression analysis revealed significant upregulation of Hoxd10, Hoxd11 and Grem1 in the anterior half of the forelimb bud at E11.5. There is also localized upregulation of Ptch1, Hand2 and Hoxd13 at the site of ectopic digit formation, indicating a posterior molecular identity for the supernumerary digits. The specific skeletal phenotypes, which include duplication of digits and distal zeugopods but no overt posteriorization, differ from those of other Twist1 conditional knockout mutants. This outcome may be attributed to the deferment of Twist1 ablation to a later time frame of limb morphogenesis, which leads to the ectopic activation of posterior genes in the anterior tissues after the establishment of anterior-posterior anatomical identities in the forelimb bud.
authors.affiliation: Embryology Unit, Children's Medical Research Institute, Westmead, New South Wales, Australia; Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: David A F
authors.initials: DA
authors.lastname: Loebel
authors.affiliation: Embryology Unit, Children's Medical Research Institute, Westmead, New South Wales, Australia.
authors.forename: Angelyn C C
authors.initials: AC
authors.lastname: Hor
authors.affiliation: Embryology Unit, Children's Medical Research Institute, Westmead, New South Wales, Australia; Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Heidi K
authors.initials: HK
authors.lastname: Bildsoe
authors.affiliation: Embryology Unit, Children's Medical Research Institute, Westmead, New South Wales, Australia; Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Patrick P L
authors.initials: PP
authors.lastname: Tam
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D019521:Body Patterning; D004622:Embryo, Mammalian / Q000378:metabolism; D047108:Embryonic Development; D005260:Female; D005552:Forelimb / Q000254:growth & development / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D018878:Limb Buds / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D010641:Phenotype; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D051879:Twist-Related Protein 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D016207:Cytokines
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface; D014157:Transcription Factors; D051879:Twist-Related Protein 1; C498766:Hand2 protein, mouse; C486697:Hoxd1 protein, mouse; C490944:Hoxd10 protein, mouse; C084118:Hoxd13 protein, mouse; C000606240:Ptch1 protein, mouse; C067250:Twist1 protein, mouse; C113178:Grem1 protein, mouse; D016207:Cytokines