Xenbase Image ID: 153583

Figure 4. A Proposed Model of Genetic Interactions that Determine Development of the L/R Axis in Mice and Humans In the mouse embryo, and most likely in humans as well, the function of several genes, including iv, inv, KIF-3A, and KIF-3B, is required for the establishment of a normal leftward flow in the node region. This nodal flow (represented by the green arrows in the node) is thought to cause the accumulation of some key extracellular determinant in the left side of the node and/or perinodal region, so that left-specific Nodal expression is induced. Expression of lefty-1 in the left side of the midline is likewise downstream of these initiating signals, but also depends on the integrity of the midline and on the activity of several genes (Brachyury, HNF-3β, Shh, and others) expressed within midline cells. In the LPM, a pathway that requires Smad-5 function (probably triggered by BMPs) acts to suppress Nodal transcription. The presence of some BMP antagonist in the left side (similar to Car in the chick) presumably acts to relieve this repression so that Nodal can be transcribed in the left LPM. Nodal, in turn, activates lefty-2 and represses SnR, in a process that requires extracellular cofactors of the EGF-CFC family, ActRIIB (not depicted here), and the intracellular factors Smad-2 and FAST2. This repression of SnR in the left side is thought to result in activation of Pitx2. At the midline, the Lefty-1 protein might act as a barrier preventing the contralateral diffusion of the proposed BMP antagonist, thus preventing ectopic expression of left-specific genes in the right side of the embryo. Note that this is a simplified model that is not intended to depict all possible interactions. For example, EGF-CFCs may be involved in mediating some earlier functions of Nodal (i.e., in the left side of the node), and the possible roles of RA and Fgf-8 as left determinants are not depicted here since their precise functions are still unclear (see main text). Image published in: Capdevila J et al. (2000) Copyright © 2000. Image reproduced with permission of the Publisher, Elsevier B. V. Larger Image Printer Friendly View

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