title: A role for the mesenchymal T-box gene Brachyury in AER formation during limb development.
abstract: During limb development, several signaling centers organize limb pattern. One of these, the apical ectodermal ridge (AER), is critical for proximodistal limb outgrowth mediated by FGFs. Signals from the underlying mesoderm, including WNTs and FGFs, regulate early steps of AER induction. Ectodermal factors, particularly En1, play a critical role in regulating morphogenesis of a mature, compact AER along the distal limb apex, from a broad ventral ectodermal precursor domain. Contribution of mesodermal factors to the morphogenesis of a mature AER is less clear. We previously noted that the chick T gene (Brachyury), the prototypical T-box transcription factor, is expressed in the limb bud as well as axial mesoderm and primitive streak. Here we show that T is expressed in lateral plate mesoderm at the onset of limb bud formation and subsequently in the subridge mesoderm beneath the AER. Retroviral misexpression of T in chick results in anterior extension of the AER and subsequent limb phenotypes consistent with augmented AER extent and function. Analysis of markers for functional AER in mouse T(-/-) null mutant limb buds reveals disrupted AER morphogenesis. Our data also suggest that FGF and WNT signals may operate both upstream and downstream of T. Taken together, the results show that T plays a role in the regulation of AER formation, particularly maturation, and suggest that T may also be a component of the epithelialmesenchymal regulatory loop involved in maintenance of a mature functioning AER.
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA.
authors.forename: Chunqiao
authors.initials: C
authors.lastname: Liu
authors.forename: Eiichiro
authors.initials: E
authors.lastname: Nakamura
authors.forename: Vladimir
authors.initials: V
authors.lastname: Knezevic
authors.forename: Sherrie
authors.initials: S
authors.lastname: Hunter
authors.forename: Katherine
authors.initials: K
authors.lastname: Thompson
authors.forename: Susan
authors.initials: S
authors.lastname: Mackem
mesh_terms: D000818:Animals; D002642:Chick Embryo; D004475:Ectoderm / Q000378:metabolism*; D005121:Extremities / Q000196:embryology*; D005326:Fetal Proteins; D005346:Fibroblast Growth Factors / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D017403:In Situ Hybridization; D008648:Mesoderm / Q000378:metabolism*; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D020825:T-Box Domain Proteins / Q000378:metabolism*; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D000098908:Brachyury Protein
chemical_list: D005326:Fetal Proteins; D005346:Fibroblast Growth Factors; D011518:Proto-Oncogene Proteins; D020825:T-Box Domain Proteins; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D000098908:Brachyury Protein