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

Dev Biol. 2012 Dec 1;372(1):55-67. doi: 10.1016/j.ydbio.2012.09.003. Epub 2012 Sep 18.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple
  • Anal Canal / abnormalities
  • Anal Canal / metabolism
  • Animals
  • Apoptosis
  • Cell Differentiation
  • Digestive System Abnormalities / genetics*
  • Digestive System Abnormalities / metabolism
  • Disease Models, Animal
  • Embryo, Mammalian / metabolism
  • Female
  • Fetal Proteins / genetics*
  • Fetal Proteins / metabolism
  • Fluorescent Antibody Technique
  • Gene Expression Regulation, Developmental
  • Meningocele
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / metabolism
  • Phenotype
  • Rectum / abnormalities
  • Rectum / metabolism
  • Sacrococcygeal Region / abnormalities
  • Sacrum / abnormalities
  • Sacrum / metabolism
  • Syringomyelia / genetics*
  • Syringomyelia / metabolism
  • T-Box Domain Proteins / genetics*
  • T-Box Domain Proteins / metabolism

Substances

  • Fetal Proteins
  • MicroRNAs
  • T-Box Domain Proteins
  • Brachyury protein

Supplementary concepts

  • Sacral defect and anterior sacral meningocele