The role of the brachyury gene in heart development and left-right specification in the mouse

The midline has a theoretical role in the development of left-right asymmet ry, and this is supported by both genetic analyses and experimental manipul ation of midline structures in vertebrates. The mouse brachyury gene encode s 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 displ aced ventricular loops, and a 50% incidence of inverted heart situs. Three TGF-beta related genes, lefty-1, lefty-2 and nodal, are expressed asymmetri cally 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 la teral 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 parch of ventral cells in, and just rostral to, the node region. These resu lts implicate the node as a source of instructive signals driving expressio n of nodal and lefty-2 in the left lateral plate mesoderm, and being requir ed for normal looping and situs of the heart. (C) 1998 Elsevier Science Ire land Ltd. All rights reserved.