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In vivo knockdown of Brachyury results in skeletal defects and urorectal malformations resembling caudal regression syndrome

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http://pubman.mpdl.mpg.de/cone/persons/resource/persons50465

Pennimpede,  Tracie
Dept. of Developmental Genetics (Head: Bernhard G. Herrmann), Max Planck Institute for Molecular Genetics, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons50388

Koenig,  Andrea
Dept. of Developmental Genetics (Head: Bernhard G. Herrmann), Max Planck Institute for Molecular Genetics, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons50435

Morkel,  Markus
Dept. of Developmental Genetics (Head: Bernhard G. Herrmann), Max Planck Institute for Molecular Genetics, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons50201

Herrmann,  Bernhard G.
Dept. of Developmental Genetics (Head: Bernhard G. Herrmann), Max Planck Institute for Molecular Genetics, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons50647

Wittler,  Lars
Transgene Unit (Head: Lars Wittler), Scientific Service (Head: Manuela B. Urban), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Citation

Pennimpede, T., Proske, J., Koenig, A., Vidigal, J. A., Morkel, M., Bramsen, J. B., et al. (2012). In vivo knockdown of Brachyury results in skeletal defects and urorectal malformations resembling caudal regression syndrome. Developmental Biology, 372(1), 55-67. doi:10.1016/j.ydbio.2012.09.003.


Cite as: http://hdl.handle.net/11858/00-001M-0000-000E-B514-D
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.