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First published online July 10, 2003
doi: 10.1242/10.1242/jcs.00668

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Left-right asymmetry: Nodal points

Stem Cell and Regeneration Program, The Burnham Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA

View larger version (45K): [in a new window]   Fig. 1. Schematic pathway for the determination of LR asymmetry. LR asymmetry proceeds from a poorly understood initial process that orients direction (1) to propagation and amplification by cascades of gene expression that culminate in production of a Nodal protein on the left side of the embryo (2). The range of Nodal action is constrained by lefty proteins, in particular at the dorsal midline. A principal function of Nodal proteins is to regulate expression of Pitx2c and other proteins that influence morphogenesis in asymmetrically developing organs (3). Modified figure reproduced, with permission, from the Nature Publishing Group (http://www.nature.com) (Hamada et al., 2002).

View larger version (26K): [in a new window]   Fig. 2. Developmental stages when the various proteins and structures are likely to contribute to LR asymmetry determination. Animal species for which the components have been examined are listed in parentheses.

View larger version (141K): [in a new window]   Fig. 3. The mouse node and monocilia. Scanning electron micrographs (provided by Daisuke Watanabe and Hiroshi Hamada, Osaka University) showing the node at the distal tip of an E8.0 mouse embryo (A). Higher magnification views show the ventral node cells (B) and individual monocilia (C). Anteroposterior body axes (A, P) and direction of flow (arrow in B) to left side (L) are indicated. Magnifications: x200 (A); x700 (B); x7000 (C).

View larger version (67K): [in a new window]   Fig. 4. Conservation of node monocilia. mRNA encoding endogenous left-right dynein (LRD), a protein involved in node monocilia in the mouse, is seen in Hensen's node in the chick, dorsal blastopore cells of the early neurula stage Xenopus, and the zebrafish shield (A,D,G,J; arrows). Monocilia are revealed on the apical surfaces of mouse ventral node cells and in cells of the related structures in chick, Xenopus and zebrafish embryos by immunostaining with anti-acetylated tubulin (B,E,H,K; arrows); a schematic representation is also shown (C,F,I,L). Reproduced, with permission, from the Nature Publishing Group (http://www.nature.com) (Essner et al., 2002).

View larger version (23K): [in a new window]   Fig. 5. Ca2+ wave model. A hypothetical model incorporates monocilia, gap junctional communication and polycystin-2 in the vicinity of the node. By analogy with Ca2+ waves in certain epithelial and endothelial cells, bending of monocilia on ventral node cells (shown for chick) are proposed to trigger a Ca2+ influx, perhaps through polycystin-2 (1), resulting in induction of a second messenger, such as Ins(1,4,5)P3, (2) that passes through gap junctions to propagate an intercellular Ca2+ wave (3) to adjacent cells. The model does not predict whether the Ca2+ wave is propagated leftwards, rightwards or both. Directional propagation would provide the simplest link to downstream gene expression and could be achieved in response to signals within the node, for instance if the monocilia sensed the leftward fluid flow [as proposed for the mouse (Tabin and Vogan, 2003)], or by the asymmetric localization of proteins, such as connexins, that are required to receive or propagate the Ca2+ signal (see text).