Vertebrate Left-Right Asymmetry: What Can Nodal Cascade Gene Expression Patterns Tell Us?

Abstract

Laterality of inner organs is a wide-spread characteristic of vertebrates and beyond. It is ultimately controlled by the left-asymmetric activation of the Nodal signaling cascade in the lateral plate mesoderm of the neurula stage embryo, which results from a cilia-driven leftward flow of extracellular fluids at the left-right organizer. This scenario is widely accepted for laterality determination in wildtype specimens. Deviations from this norm come in different flavors. At the level of organ morphogenesis, laterality may be inverted (situs inversus) or non-concordant with respect to the main body axis (situs ambiguus or heterotaxia). At the level of Nodal cascade gene activation, expression may be inverted, bilaterally induced, or absent. In a given genetic situation, patterns may be randomized or predominantly lacking laterality (absence or bilateral activation). We propose that the distributions of patterns observed may be indicative of the underlying molecular defects, with randomizations being primarily caused by defects in the flow-generating ciliary set-up, and symmetrical patterns being the result of impaired flow sensing, on the left, the right, or both sides. This prediction, the reasoning of which is detailed in this review, pinpoints functions of genes whose role in laterality determination have remained obscure.

Keywords: Nodal; Nodal cascade; cilia; heterotaxia; left-right asymmetry; left-right organizer; leftward flow; situs ambiguus; situs inversus; symmetry breaking.

Figure 1

Expression patterns of Nodal cascade genes. Shown are Pitx2 gene expression patterns in Xenopus tadpoles that can be wildtype (A), inverted (B), bilateral (C), or absent (D) on both sides, such as encountered in mutants and morphants of the dynein motor protein defective in iv mutant mice.

Figure 2

Schematic depiction of left-right (LR) axis specification in vertebrate embryos that use a ciliated left-right organizer (LRO) to break the bilateral symmetry of the early embryo. For a detailed discussion, see main text.