Chu Gerald C, Dunn N Ray, Anderson Dorian C, Oxburgh Leif, Robertson Elizabeth J
Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.
Development. 2004 Aug;131(15):3501-12. doi: 10.1242/dev.01248. Epub 2004 Jun 23.
Genetic and biochemical data have identified Smad4 as a key intracellular effector of the transforming growth factor beta (TGFbeta superfamily of secreted ligands. In mouse, Smad4-null embryos do not gastrulate, a phenotype consistent with loss of other TGFbeta-related signaling components. Chimeric analysis reveals a primary requirement for Smad4 in the extra-embryonic lineages; however, within the embryo proper, characterization of the specific roles of Smad4 during gastrulation and lineage specification remains limited. We have employed a Smad4 conditional allele to specifically inactivate the Smad4 gene in the early mouse epiblast. Loss of Smad4 in this tissue results in a profound failure to pattern derivatives of the anterior primitive streak, such as prechordal plate, node, notochord and definitive endoderm. In contrast to these focal defects, many well-characterized TGFbeta- and Bmp-regulated processes involved in mesoderm formation and patterning are surprisingly unaffected. Mutant embryos form abundant extra-embryonic mesoderm, including allantois, a rudimentary heart and middle primitive streak derivatives such as somites and lateral plate mesoderm. Thus, loss of Smad4 in the epiblast results not in global developmental abnormalities but instead in restricted patterning defects. These results suggest that Smad4 potentiates a subset of TGFbeta-related signals during early embryonic development, but is dispensable for others.
遗传学和生物化学数据已确定Smad4是转化生长因子β（TGFβ，一个分泌配体的超家族）的关键细胞内效应因子。在小鼠中，Smad4基因敲除的胚胎无法进行原肠胚形成，该表型与其他TGFβ相关信号成分的缺失一致。嵌合体分析揭示了胚外谱系中对Smad4的主要需求；然而，在胚胎本身中，Smad4在原肠胚形成和谱系特化过程中的具体作用仍知之甚少。我们利用一个Smad4条件等位基因在小鼠早期上胚层中特异性地使Smad4基因失活。该组织中Smad4的缺失导致前原条衍生物（如脊索前板、节点、脊索和定形内胚层）的模式形成严重失败。与这些局部缺陷相反，许多参与中胚层形成和模式形成的、已被充分表征的TGFβ和Bmp调节过程出人意料地未受影响。突变胚胎形成了丰富的胚外中胚层，包括尿囊、一个原始心脏以及中原始条衍生物（如体节和侧板中胚层）。因此，上胚层中Smad4的缺失并非导致整体发育异常，而是导致局限性的模式形成缺陷。这些结果表明，Smad4在早期胚胎发育过程中增强了一部分TGFβ相关信号，但对其他信号则是可有可无的。
