Man1, an inner nuclear membrane protein, regulates left-right axis formation by controlling nodal signaling in a node-independent manner

Dev Dyn. 2008 Dec;237(12):3565-76. doi: 10.1002/dvdy.21663.


Man1, an inner nuclear membrane protein, regulates transforming growth factor beta signaling by interacting with receptor-associated Smads. In Man1-deficient (Man1(Delta/Delta)) embryos, vascular remodeling is perturbed by misregulation of Smad activity. Here, we show that Man1(Delta/Delta) embryos exhibit abnormal heart morphogenesis including the looping abnormality. We searched for the molecular basis underlying the heart abnormalities and found that the left side-specific genes responsible for left-right (LR) asymmetry, Nodal, Lefty2, and Pitx2, were expressed bilaterally in the lateral plate mesoderm and that their expression was enhanced significantly in mutants. Notably, Lefty1, a marker for the midline barrier, was maintained in Man1(Delta/Delta) mutants. Crossing Man1(Delta/+) with Nodal hypomorphs (Nodal(neo/+)), in which Nodal signaling in the node is disrupted, to generate double homozygous embryos (Man1(Delta/Delta); Nodal(neo/neo)) revealed that the bilateral Nodal was retained in Man1(Delta/Delta); Nodal(neo/neo) embryos. These results suggest that Man1 regulates LR asymmetry by controlling Nodal signaling in a node-independent manner.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Fluids
  • Body Patterning*
  • Bone Morphogenetic Protein 2 / metabolism
  • DNA-Binding Proteins
  • Gene Expression Regulation, Developmental
  • Heart / embryology
  • Membrane Proteins / deficiency
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Microscopy, Electron, Scanning
  • Myocardium / metabolism
  • Nodal Protein / genetics
  • Nodal Protein / metabolism*
  • Nuclear Proteins / deficiency
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Signal Transduction*


  • Bmp2 protein, mouse
  • Bone Morphogenetic Protein 2
  • DNA-Binding Proteins
  • Man1 protein, mouse
  • Membrane Proteins
  • Nodal Protein
  • Nuclear Proteins