Fig. 1.

Schematic of cytoplasmic model of left–right (LR) asymmetry. This schematization, based on events characterized in Xenopus laevis, shows how intracellular chirality can be imposed upon multicellular cell fields, and initiate asymmetric gene expression relative to the midline, by a physiological mechanism driven by maternal, biophysical events. A: Eggs are initially loaded with maternal mRNAs and proteins (blue) that are symmetrically (radially) distributed around the animal–vegetal axis. B: When the egg is fertilized, the location of the sperm entry point dictates the location of the first cleavage plane, which usually coincides with the midline of the developing animal (Scharf and Gerhart, 1983; Ubbels et al., 1983; Klein, 1987; Masho, 1990; Marrari et al., 2004) . The crucial event at this stage is the complex set of known cytoskeletal rearrangements that include the hypothetical orientation of an organizing center (e.g., the centrioles existing at right angles to each other) with respect to the animal–vegetal and dorsal–ventral axes (the enantiomeric “F-molecule,” here represented by a hand). Maternal cargo proteins/mRNAs can then begin to be distributed in a consistently-asymmetric manner by cytoplasmic motor transport (dependent on kinesin, dynein, and microtubule arrays). C: By the four-cell stage, maternal mRNAs are now largely localized to the right ventral blastomere. These mRNAs encode ion transporters including two potassium channels (Aw et al., 2008; Morokuma et al., 2008) and two proton pumps, the H⁺-K⁺-ATPase (Levin et al., 2002) and the H⁺-V-ATPase (Adams et al., 2006). D: Together, the asymmetric localization of these transporters (blue circles) leads to a circuit establishing physiological asymmetries such as an increased pumping of positively charged ions out of the right side cell (+), leading to a difference in transmembrane potential between the L and R blastomeres across the ventral midline. The blastomeres of the early embryo next become connected by means of open gap junctions (orange channels), with the exception of the cells between the left and right ventral cells (Levin and Mercola, 1998b), which are junctionally-isolated (dark line). E: Serotonin and perhaps other small charged morphogens (yellow dots) are initially present in all blastomeres. F: Subject to selectivity of the gap junctions, some are then driven toward the right-most ventral cell by an electrophoretic force maintained by the battery at the ventral edge. G,H: Through an as-yet uncharacterized pathway, the localization of morphogens such as serotonin to the right side of the embryo suppresses downstream expression of genes (i.e., Nodal), which are thus expressed only on the left side (G), which eventually leads to asymmetric organ morphogenesis (H). This model can be readily extended to bodyplans where the midline is defined after the initial cleavages are complete by the spread of LR orientation information from coordinator cell(s) by means of planar cell polarity pathways (Aw and Levin, 2009; Vandenberg and Levin, 2010).