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THE EMBRYONIC ORIGINS OF LEFT-RIGHT ASYMMETRY

Cytokine Biology Dept., The Forsyth Institute, and Department of Craniofacial and Developmental Biology, Harvard School of Dental Medicine, 140 The Fenway, Boston, MA 02115; mlevin{at}forsyth.org

View larger version (29K): [in a new window]   Figure 1. The Brown and Wolpert chiral molecule model. (A) In two dimensions, a biological molecule which occurs only as one enantiomer (schematized by the letter ‘F’) can be tethered with respect to one dimension (e.g., anterior-posterior). The chirality of the molecule then defines a left-right direction, which can provide asymmetrical information, such as the rightward transport of some determinant (schematized in red). (B,C) In three dimensions, the same mechanism can function in a cell that is molecularly polarized along, and can orient the chiral molecule with respect to, the anterior-posterior and dorso-ventral axes. This type of mechanism allows each cell to know which direction is Left and which is Right.

View larger version (59K): [in a new window]   Figure 2. Direction vs. position on the Left-Right axis. (A) A tethered chiral structure can give information as to which direction is Right or Left. However, gastrulating embryos exhibit paired cell fields on either side of the midline, only one of which expresses certain genes. (B) For example, Nodal, a TGF-ß family member, is expressed in a small and large domain (green arrows) on only one side of the midline. This requires that cells know their position with respect to the midline; this information is different from direction, and requires coordination with respect to the whole embryo (in contrast to the localized directional information generated by a chiral molecule).

View larger version (58K): [in a new window]   Figure 3. A model of the LR pathway based on cytoplasmic motor protein movement. This highly schematized diagram draws mainly on Xenopus embryogenesis and attempts to follow known timing data for each step. (A) In the unfertilized egg (which is thought to possess radial symmetry about the animal-vegetal axis), maternal mRNAs for key ion transporters are evenly distributed. (B) Cytoskeletal re-arrangements following fertilization set up microfilaments or microtubules which are oriented along the newly established LR axis. (C) Motor proteins (such as dynein [LRD] and kinesin [KIF-3B]) translocate along these tracks and result in an asymmetric localization of certain mRNAs. (D) These mRNAs are translated, the resulting proteins perhaps targeted to correct regions and held in place by ankyrin proteins such as inv, and thus initiate ion flux. (E) The differential ion flux results in LR-asymmetric gradients of pH and voltage. In particular, cells across the ventral midline possess significantly different membrane potential levels. (F) The system of gap-junctional communication is set up, featuring junctional isolation across the ventral midline and a path of GJC circumferentially around it. (G) The voltage gradient between the L and R sides imposes a unidirectional net movement of as-yet-uncharacterized small signaling molecules. This results in accumulation on one side of the midline from an initially random (homogenous) distribution. (H) The accumulation of these small molecule morphogens on one side induces gene expression in conventional ways. (I) This initiates the known cascade of asymmetrically expressed signaling factors which form the middle of the LR pathway which dictates the situs of asymmetric organs.