title: Disrupting the establishment of polarizing activity by teratogen exposure.
abstract: Between days 9.5 and 10, the forelimb buds of developing murine embryos progress from stage 1 which are just beginning to express shh and whose posterior mesoderm has only weak polarizing activity to stage 2 limbs with a distinguishable shh expression domain and full polarizing activity. We find that exposure on day 9.5 to teratogens that induce the loss of posterior skeletal elements disrupts the polarizing activity of the stage 2 postaxial mesoderm and polarizing activity is not subsequently restored. The ontogeny of expression of the mesodermal markers shh, ptc, bmp2, and hoxd-12 and 13, as well as the ectodermal markers wnt7a, fgf4, fgf8, cx43, and p21 occurred normally in day 9.5 teratogen-exposed limb buds. At stage 3, the treated limb apical ectodermal ridge usually possessed no detectable abnormalities, but with continued outgrowth postaxial deficiencies became evident. Recombining control, stage matched limb bud ectoderm with treated mesoderm prior to ZPA grafting restored the duplicating activity of treated ZPA tissue. We conclude that in addition to shh an early ectoderm-dependent signal is required for the establishment of the mouse ZPA and that this factor is dependent on the posterior ectoderm.
authors.affiliation: Children's Hospital Research Foundation, Division of Developmental Biology, 3333 Burnet Avenue, Cincinnati, OH 45229, USA. sheila.bell@chmcc.org
authors.forename: S M
authors.initials: SM
authors.lastname: Bell
authors.forename: C M
authors.initials: CM
authors.lastname: Schreiner
authors.forename: W J
authors.initials: WJ
authors.lastname: Scott
mesh_terms: D000086:Acetazolamide / Q000633:toxicity; D000584:Amiloride / Q000031:analogs & derivatives / Q000633:toxicity; D000818:Animals; D019521:Body Patterning / Q000187:drug effects*; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000187:drug effects / Q000235:genetics; D004475:Ectoderm / Q000187:drug effects / Q000637:transplantation; D004622:Embryo, Mammalian / Q000187:drug effects*; D005121:Extremities / Q000196:embryology*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins / Q000187:drug effects / Q000235:genetics; D018878:Limb Buds / Q000002:abnormalities / Q000187:drug effects; D017880:Limb Deformities, Congenital / Q000139:chemically induced; D008565:Membrane Proteins / Q000187:drug effects / Q000235:genetics; D008648:Mesoderm / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009024:Morphogenesis; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011247:Pregnancy; D011506:Proteins / Q000187:drug effects / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000235:genetics; D011956:Receptors, Cell Surface; D013723:Teratogens / Q000633:toxicity*; D016378:Tissue Transplantation; D015534:Trans-Activators; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics; D016212:Transforming Growth Factor beta; D051153:Wnt Proteins
chemical_list: C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; C490943:Hoxd12 protein, mouse; C084118:Hoxd13 protein, mouse; D008565:Membrane Proteins; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011506:Proteins; D011518:Proto-Oncogene Proteins; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D013723:Teratogens; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D051153:Wnt Proteins; C490508:Wnt7a protein, mouse; C013407:benzamil; D000584:Amiloride; D000086:Acetazolamide