title: In vivo knockdown of Brachyury results in skeletal defects and urorectal malformations resembling caudal regression syndrome.
abstract: The T-box transcription factor BRACHYURY (T) is a key regulator of mesoderm formation during early development. Complete loss of T has been shown to lead to embryonic lethality around E10.0. Here we characterize an inducible miRNA-based in vivo knockdown mouse model of T, termed KD3-T, which exhibits a hypomorphic phenotype. KD3-T embryos display axial skeletal defects caused by apoptosis of paraxial mesoderm, which is accompanied by urorectal malformations resembling the murine uro-recto-caudal syndrome and human caudal regression syndrome phenotypes. We show that there is a reduction of T in the notochord of KD3-T embryos which results in impaired notochord differentiation and its subsequent loss, whereas levels of T in the tailbud are sufficient for axis extension and patterning. Furthermore, the notochord in KD3-T embryos adopts a neural character and loses its ability to act as a signaling center. Since KD3-T animals survive until birth, they are useful for examining later roles for T in the development of urorectal tissues.
authors.affiliation: Max Planck Institute for Molecular Genetics, Developmental Genetics Department, Ihnestraße 73, 14195 Berlin, Germany.
authors.forename: Tracie
authors.initials: T
authors.lastname: Pennimpede
authors.forename: Judith
authors.initials: J
authors.lastname: Proske
authors.forename: Andrea
authors.initials: A
authors.lastname: König
authors.forename: Joana A
authors.initials: JA
authors.lastname: Vidigal
authors.forename: Markus
authors.initials: M
authors.lastname: Morkel
authors.forename: Jesper B
authors.initials: JB
authors.lastname: Bramsen
authors.forename: Bernhard G
authors.initials: BG
authors.lastname: Herrmann
authors.forename: Lars
authors.initials: L
authors.lastname: Wittler
mesh_terms: D000015:Abnormalities, Multiple; D001003:Anal Canal / Q000002:abnormalities / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D004065:Digestive System Abnormalities / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D004622:Embryo, Mammalian / Q000378:metabolism; D005260:Female; D005326:Fetal Proteins / Q000235:genetics* / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D018507:Gene Expression Regulation, Developmental; D008588:Meningocele; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism; D010641:Phenotype; D012007:Rectum / Q000002:abnormalities / Q000378:metabolism; D012445:Sacrococcygeal Region / Q000002:abnormalities; D012447:Sacrum / Q000002:abnormalities / Q000378:metabolism; D013595:Syringomyelia / Q000235:genetics* / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000235:genetics* / Q000378:metabolism; D000098908:Brachyury Protein
chemical_list: D005326:Fetal Proteins; D035683:MicroRNAs; D020825:T-Box Domain Proteins; D000098908:Brachyury Protein