title: Tbx5 is essential for forelimb bud initiation following patterning of the limb field in the mouse embryo.
abstract: Transcriptional cascades responsible for initiating the formation of vertebrate embryonic structures such as limbs are not well established. Limb formation occurs as a result of interplay between fibroblast growth factor (FGF) and Wnt signaling. What initiates these signaling cascades and thus limb bud outgrowth at defined locations along the anteroposterior axis of the embryo is not known. The T-box transcription factor TBX5 is important for normal heart and limb formation, but its role in early limb development is not well defined. We report that mouse embryos lacking Tbx5 do not form forelimb buds, although the patterning of the lateral plate mesoderm into the limb field is intact. Tbx5 is not essential for an early establishment of forelimb versus hindlimb identity. In the absence of Tbx5, the FGF and Wnt regulatory loops required for limb bud outgrowth are not established, including initiation of Fgf10 expression. Tbx5 directly activates the Fgf10 gene via a conserved binding site, providing a simple and direct mechanism for limb bud initiation. Lef1/Tcf1-dependent Wnt signaling is not essential for initiation of Tbx5 or Fgf10 transcription, but is required in concert with Tbx5 for maintenance of normal levels of Fgf10 expression. We conclude that Tbx5 is not essential for the early establishment of the limb field in the lateral plate mesoderm but is a primary and direct initiator of forelimb bud formation. These data suggest common pathways for the differentiation and growth of embryonic structures downstream of T-box genes.
authors.affiliation: Programmes in Cardiovascular Research and Developmental Biology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
authors.forename: Pooja
authors.initials: P
authors.lastname: Agarwal
authors.forename: John N
authors.initials: JN
authors.lastname: Wylie
authors.forename: Juan
authors.initials: J
authors.lastname: Galceran
authors.forename: Oksana
authors.initials: O
authors.lastname: Arkhitko
authors.forename: Cuiling
authors.initials: C
authors.lastname: Li
authors.forename: Chuxia
authors.initials: C
authors.lastname: Deng
authors.forename: Rudolf
authors.initials: R
authors.lastname: Grosschedl
authors.forename: Benoit G
authors.initials: BG
authors.lastname: Bruneau
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000235:genetics / Q000502:physiology; D051526:Fibroblast Growth Factor 10; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000502:physiology; D005552:Forelimb / Q000196:embryology*; D018507:Gene Expression Regulation, Developmental; D006614:Hindlimb / Q000196:embryology; D017880:Limb Deformities, Congenital / Q000196:embryology / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051153:Wnt Proteins; D029961:Zebrafish Proteins
chemical_list: C496464:Fgf10 protein, mouse; D051526:Fibroblast Growth Factor 10; D011518:Proto-Oncogene Proteins; D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D005346:Fibroblast Growth Factors