King T, Beddington R S, Brown N A
Department of Anatomy and Developmental Biology, St George's Hospital Medical School, London, UK.
Mech Dev. 1998 Dec;79(1-2):29-37. doi: 10.1016/s0925-4773(98)00166-x.
The midline has a theoretical role in the development of left-right asymmetry, and this is supported by both genetic analyses and experimental manipulation of midline structures in vertebrates. The mouse brachyury (T) gene encodes a transcription factor which is expressed in the developing notochord and is required for its development. T/T mice lack a mature notochord and have a dorsalised neural tube. We have examined the hearts of T/T mice and have found consistent morphological abnormalities, resulting in ventrally displaced ventricular loops, and a 50% incidence of inverted heart situs. Three TGF-beta related genes, lefty-1, lefty-2 and nodal, are expressed asymmetrically in mouse embryos, and are implicated in the development of situs. We find that nodal, which is normally expressed around the node and in left lateral plate mesoderm in early somite embryos, is completely absent at this stage in T/T embryos. In contrast, lefty-1 and lefty-2, which are normally expressed in the left half of prospective floorplate and left lateral plate mesoderm, respectively, are both expressed in T/T embryos only in a broad patch of ventral cells in, and just rostral to, the node region. These results implicate the node as a source of instructive signals driving expression of nodal and lefty-2 in the left lateral plate mesoderm, and being required for normal looping and situs of the heart.
中线在左右不对称发育中具有理论作用，这一点在脊椎动物中线结构的遗传分析和实验操作中均得到支持。小鼠短尾（T）基因编码一种转录因子，该转录因子在发育中的脊索中表达，是脊索发育所必需的。T/T小鼠缺乏成熟的脊索，且神经管背化。我们检查了T/T小鼠的心脏，发现了一致的形态学异常，导致心室环腹侧移位，心脏位置反转的发生率为50%。三个与转化生长因子β相关的基因，即左撇子-1、左撇子-2和节点蛋白，在小鼠胚胎中不对称表达，并与内脏位置的发育有关。我们发现，在早期体节胚胎中通常在节点周围和左侧板中胚层表达的节点蛋白，在T/T胚胎的这个阶段完全缺失。相反，通常分别在前庭底板左半部分和左侧板中胚层表达的左撇子-1和左撇子-2，在T/T胚胎中仅在节点区域内及其前方的一大片腹侧细胞中表达。这些结果表明，节点是驱动左侧板中胚层中节点蛋白和左撇子-2表达的指导性信号来源，并且是心脏正常环化和内脏位置所必需的。
