Left-right asymmetry

Left-right asymmetry (LR asymmetry) refers to differences in structure (symmetry breaking) across the mediolateral (left and right) plane in animals. This plane is defined with respect to the anteroposterior and dorsoventral axes and is perpendicular to both. Because the left-right plane is not strictly an axis (as it is not established through a morphogen gradient), to create asymmetry, the left and right sides need to be patterned separately.^[1]

LR asymmetry is pervasive throughout metazoans and present throughout every major lineage. Notable examples include the large and small claws of the fiddler crab, the left offset of the vertebrate heart, asymmetrical gut coiling in Drosophila melanogaster, and dextral (clockwise) and sinistral (counterclockwise) coiling of gastropods. This asymmetry can be restricted to a specific organ or feature, as in the crab claws, or be expressed throughout the entire body as in snails.

Developmental basis

Components of the Nodal signaling pathway have been implicated in left-right determination in a diverse set of taxa.^[2][3] While the mechanisms to set up the left-right sides appear to differ markedly among groups of organisms, Nodal is consistently deployed in most of the lineages that have been examined (except for ecdysozoans).^[3] In established model organisms such as mouse, chick, D. melanogaster, and Xenopus, ongoing research has begun to focus on cellular level symmetry-breaking mechanisms (e.g. cytoskeletal chirality, ciliary flow) that may lead to differential expression of molecules such as Nodal.^[4]

Vertebrates

Nodal was first described in the chick embryo, where genes activin receptor IIa, Sonic hedgehog (Shh), and chick nodal-related 1 (cNR-1) were found to be asymmetrically expressed across Hensen's node with cnR-1 expressed on the left side.^[2] Misexpressing Shh or activin receptor IIa on the right side randomized heart asymmetry in the chick. This asymmetrical gene expression appears to be triggered by cell movements in the node.^[5]

In mouse, the left side is distinguished from the right through Nodal flow.^[6] Originally described from inversus viscerum (iv) and inversion of embryonic turning (inv) mouse mutants, which are characterized by a randomization of left-right phenotypes, Nodal flow refers to the movement of nodal cilia to create a leftward flow of extraembryonic fluid.^[7] Carried in this leftward movement is Nodal, a signaling peptide from the TGF-β family necessary to pattern left-right determination.^[8] In the lateral plate mesoderm, Nodal then activates a positive feedback loop promoting its expression and its downstream effector Pitx2. To prevent expansion to the rightward portion of the embryo, Nodal activates Lefty1 and Lefty2, which repress the Nodal signaling pathway by competing with Nodal binding sites.^[9]

Because Nodal flow through ciliary movement is not present in all vertebrates (e.g. the chick), asymmetric gene expression must be established in another way. One such idea posits that ion channels and pumps (H+/K+ ATPase) generate differences in voltage and pH across the mediolateral plane, thus providing gradients to orient signaling molecules.^[10]

Non-vertebrate deuterostomes

Recently, work has shown that the Nodal-Pitx2 pathway is present and functional in the non-vertebrate deuterostomes (tunicates, sea urchins).^[11][12] In tunicate (ascidian) Ciona intestinalis and Halocynthia roretzi, Nodal is expressed on the left side of the developing embryo and leads to downstream expression of Pitx2. At earlier stages, similar H+/K+ ATPase ion channels are reported to be necessary for correct left-right patterning.^[11] While the role of cilia here is still unclear, one study observes that large-scale embryonic movements are required for left-right determination in H. roretzi, and that this movement is possibly achieved through ciliary movements.^[13]

In the sea urchin, Nodal is expressed on the right side of the embryo, in contrast to the tunicate and vertebrate condition on the left side.^[12] Because protostomes appear to also express Nodal on their right side instead of the left (discussed below), some have suggested that this lends further evidence for the dorsoventral inversion hypothesis.^[3]

Protostomes

Ecdysozoa

While D. melanogaster and nematode Caenorhabditis elegans do show left-right asymmetry, the Nodal signaling pathway itself is absent in Ecdysozoa.^[3] Instead, cytoskeletal regulators such as Myo31DF, a type ID unconventional myosin, have been found to control left-right asymmetry in organ systems such as genitalia.^[14]

Lophotrochozoa

Unlike in Ecdysozoa, the Nodal-Pitx2 pathways have been identified in many lineages within the Lophotrochozoans.^[15] When found in brachiopods and molluscs, these genes are asymmetrically expressed on the right.^[15] Platyhelminthes, annelids, and nermeteans lack a Nodal orthologue and instead only express Pitx2, which was expressed in association to the nervous system.^[15]

Whole body left-right asymmetry in gastropods

Whole body inversion is observed as chiral (dextral, sinistral) coiling in gastropods. While dextral coiling is the most common as it appears in 90-99% of living species, sinistral species still have arisen many times.^[16]

Developmental basis of shell coiling

Gastropods undergo spiral cleavage, a feature commonly seen in lophotrochozoans. As the embryo divides, quartets of cells are oriented at angles to each other. In the snail Lymnaea stagnalis, the direction of rotation during the first cell division signals whether the adult will show dextral or sinistral coiling,^[17] At the third cleavage (8-cell stage), spindles in dextral snails are inclined clockwise whereas they are counterclockwise in sinistral snails.^[18] Furthermore, injecting L. peregra sinistral eggs with the cytoplasm of dextral eggs before the second polar body formation will reverse the polarity of the sinistral embryos.^[19] These data show that chirality is heritable and maternally deposited in Lymnaea.^[17][18][19]

Several studies have begun to investigate the molecular basis of this inheritance. Nodal and Pitx2 are expressed on different sides of the L. stagnalis embryo depending on its chirality – right for dextral, left for sinistral.^[20] Downstream of Nodal, decapentaplegic (dpp), shows the same expression pattern.^[21] In limpets (gastropods without coiled shells) dpp is expressed symmetrically in Patella vulgata and Nipponacmea fuscoviridis.^[21] Additionally, in N. fuscoviridis, dpp has been shown to drive cell proliferation^[22]

Upstream of Nodal, Lsdia1/2 have been implicated in controlling L. stagnalis chirality.^[23][24] Davison et al. (2016) mapped the “chirality locus” to a 0.4 Mb region and determined that Lsdia2 is the likely candidate for determining dextral or sinistral coiling.^[23] This is a diaphanous-related formin gene involved in cytoskeleton formation.^[23] Dextral embryos treated with drugs that inhibited formin activity phenocopied the sinistral condition. Concurrent work from Kuroda et al. (2016) identified the same Lsdia2 gene (called Lsdia1 in their study) but failed to reproduce the formin inhibition results in the Davison et al. study.^[24] Additionally, Kuroda et al. (2016) did not find asymmetrically expressed Lsdia2 as was seen in the Davison et al. (2016) study.

References

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