Ishimura Akihiko, Chida Shinsuke, Osada Shin-Ichi
The 21st Century Center of Excellence (COE) Program, Akita University, Akita, Japan.
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.
Man1是一种内核膜蛋白，通过与受体相关的Smads相互作用来调节转化生长因子β信号通路。在Man1缺陷型（Man1(Delta/Delta)）胚胎中，血管重塑因Smad活性的失调而受到干扰。在此，我们表明Man1(Delta/Delta)胚胎表现出异常的心脏形态发生，包括心脏环化异常。我们探寻了心脏异常背后的分子基础，发现负责左右（LR）不对称性的左侧特异性基因Nodal、Lefty2和Pitx2在侧板中胚层中双侧表达，并且它们在突变体中的表达显著增强。值得注意的是，中线屏障的标志物Lefty1在Man1(Delta/Delta)突变体中得以维持。将Man1(Delta/+)与节点中Nodal信号传导被破坏的Nodal低表达体（Nodal(neo/+))杂交，以产生双纯合胚胎（Man1(Delta/Delta); Nodal(neo/neo)），结果显示双侧Nodal在Man1(Delta/Delta); Nodal(neo/neo)胚胎中得以保留。这些结果表明，Man1通过以不依赖节点的方式控制Nodal信号传导来调节左右不对称性。
