Left-right asymmetry (LR asymmetry) is the process in early embryonic development that breaks the normal symmetry in the bilateral embryo. In vertebrates, left-right asymmetry is established early in development at a structure called the left-right organizer (the name of which varies between species) and leads to activation of different signalling pathways on the left and right of the embryo.[1] This in turn cause several organs in adults to develop LR asymmetry, such as the tilt of the heart, the different number lung lobes on each side of the body and the position of the stomach and spleen on the right side of the body.[2] If this process does not occur correctly in humans it can result in the syndromes heterotaxy or situs inversus.

LR asymmetry is pervasive throughout all animals, including invertebrates. Examples of invertebrate LR asymmetry include the large and small claws of the fiddler crab, 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

Different species have evolved different mechanisms of LR patterning. For example, cilia are critical for LR patterning in many vertebrate species such as humans, rodents, fish and frog, but other species, such as reptiles, birds and pigs develop LR asymmetry without cilia.[3]

Cilia dependent vertebrates

The name of the LR organiser varies between species, and thus includes the node in mice, the gastrocoel roof plate in frog and Kupffer’s vesicle in zebrafish.[4] In each case the LR organizer is found on the dorsal side of the embryo and each organizer cell has a single cilia located on the posterior side of the cell. The combination of location of cells of the dorsal surface combined with the posterior location of the cilia means that when the cilia rotate it creates a left-ward flow across the surface of the organizer.[5] The flow causes loss of Cerl2 and increased Nodal expression on the left side of the organizer, although there is some debate whether this occurs due to a chemical/protein signal or due to the cells physically sensing the flow.[1] In either case, the signal is then transferred to the left Lateral plate mesoderm where it activates a further signalling cascade of genes including Nodal, Pitx2 and Lefty2.

Cilia independent vertebrates

In chickens, LR asymmetry is established at a structure called Hensen’s node. Unlike most other vertebrates, this process is not thought to involve cilia as (i) Hensen’s node does not have motile cilia and (ii) unlike other species, mutations that affect cilia formation do not cause laterality defects in chicken.[6] Instead, chickens establish LR asymmetry through asymmetric cell rearrangements which results in a leftward movement of cells near the Hensen’s node.[7]

Another study has found that pigs do not have cilia within their left right organiser, suggesting pigs also have an alternative cilia independent mechanism for establishing LR asymmetry.[8]

Non-vertebrate deuterostomes

Recently, work has shown that the Nodal-Pitx2 pathway is present and functional in the non-vertebrate deuterostomes (tunicates, sea urchins).[9][10] 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.[9] 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.[11]

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.[10] 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.[12]

Protostomes

Ecdysozoa

While D. melanogaster and nematode Caenorhabditis elegans do show left-right asymmetry, the Nodal signaling pathway itself is absent in Ecdysozoa.[12] 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.[13]

Lophotrochozoa

Unlike in Ecdysozoa, the Nodal-Pitx2 pathways have been identified in many lineages within the Lophotrochozoans.[14] When found in brachiopods and molluscs, these genes are asymmetrically expressed on the right.[14] Platyhelminthes, annelids, and nermeteans lack a Nodal orthologue and instead only express Pitx2, which was expressed in association to the nervous system.[14]

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.[15]

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,[16] At the third cleavage (8-cell stage), spindles in dextral snails are inclined clockwise whereas they are counterclockwise in sinistral snails.[17] 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.[18] These data show that chirality is heritable and maternally deposited in Lymnaea.[16][17][18]

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.[19] Downstream of Nodal, decapentaplegic (dpp), shows the same expression pattern.[20] In limpets (gastropods without coiled shells) dpp is expressed symmetrically in Patella vulgata and Nipponacmea fuscoviridis.[20] Additionally, in N. fuscoviridis, dpp has been shown to drive cell proliferation[21]

Upstream of Nodal, Lsdia1/2 have been implicated in controlling L. stagnalis chirality.[22][23] 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.[22] This is a diaphanous-related formin gene involved in cytoskeleton formation.[22] 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.[23] Additionally, Kuroda et al. (2016) did not find asymmetrically expressed Lsdia2 as was seen in the Davison et al. (2016) study.

See also

References

  1. 1 2 Little, RB; Norris, DP (February 2021). "Right, left and cilia: How asymmetry is established". Seminars in Cell & Developmental Biology. 110: 11–18. doi:10.1016/j.semcdb.2020.06.003. PMID 32571625. S2CID 219984175.
  2. ↑ Blum, M; Ott, T (2 April 2018). "Animal left-right asymmetry". Current Biology. 28 (7): R301–R304. doi:10.1016/j.cub.2018.02.073. PMID 29614284. S2CID 4613375.
  3. ↑ Hamada, H; Tam, P (2020). "Diversity of left-right symmetry breaking strategy in animals". F1000Research. 9: 123. doi:10.12688/f1000research.21670.1. PMC 7043131. PMID 32148774.
  4. ↑ Blum, M; Feistel, K; Thumberger, T; Schweickert, A (April 2014). "The evolution and conservation of left-right patterning mechanisms". Development. 141 (8): 1603–13. doi:10.1242/dev.100560. PMID 24715452. S2CID 871667.
  5. ↑ Hamada, H; Tam, PP (2014). "Mechanisms of left-right asymmetry and patterning: driver, mediator and responder". F1000Prime Reports. 6: 110. doi:10.12703/P6-110. PMC 4275019. PMID 25580264.
  6. ↑ Dasgupta, Agnik; Amack, Jeffrey D. (19 December 2016). "Cilia in vertebrate left–right patterning". Philosophical Transactions of the Royal Society B: Biological Sciences. 371 (1710): 20150410. doi:10.1098/rstb.2015.0410. PMC 5104509. PMID 27821522.
  7. ↑ Gros, Jerome; Feistel, Kerstin; Viebahn, Christoph; Blum, Martin; Tabin, Clifford J. (15 May 2009). "Cell Movements at Hensen's Node Establish Left/Right Asymmetric Gene Expression in the Chick". Science. 324 (5929): 941–944. Bibcode:2009Sci...324..941G. doi:10.1126/science.1172478. PMC 2993078. PMID 19359542.
  8. ↑ Hamada, Hiroshi; Tam, Patrick (19 February 2020). "Diversity of left-right symmetry breaking strategy in animals". F1000Research. 9: 123. doi:10.12688/f1000research.21670.1. PMC 7043131. PMID 32148774.
  9. 1 2 Shimeld, Sebastian M.; Levin, Michael (2006-06-01). "Evidence for the regulation of left-right asymmetry in Ciona intestinalis by ion flux". Developmental Dynamics. 235 (6): 1543–1553. doi:10.1002/dvdy.20792. ISSN 1097-0177. PMID 16586445.
  10. 1 2 Molina, M Dolores; de Crozé, Noémie; Haillot, Emmanuel; Lepage, Thierry (2013-08-01). "Nodal: master and commander of the dorsal–ventral and left–right axes in the sea urchin embryo". Current Opinion in Genetics & Development. Developmental mechanisms, patterning and evolution. 23 (4): 445–453. doi:10.1016/j.gde.2013.04.010. PMID 23769944.
  11. ↑ Nishide, Kazuhiko; Mugitani, Michio; Kumano, Gaku; Nishida, Hiroki (2012-04-15). "Neurula rotation determines left-right asymmetry in ascidian tadpole larvae". Development. 139 (8): 1467–1475. doi:10.1242/dev.076083. ISSN 0950-1991. PMID 22399684.
  12. 1 2 Coutelis, J. B., González‐Morales, N., Géminard, C., & Noselli, S. (2014). Diversity and convergence in the mechanisms establishing L/R asymmetry in metazoa. EMBO Reports, e201438972.
  13. ↑ Spéder, Pauline; Ádám, Géza; Noselli, Stéphane (2006-04-06). "Type ID unconventional myosin controls left–right asymmetry in Drosophila". Nature. 440 (7085): 803–807. Bibcode:2006Natur.440..803S. doi:10.1038/nature04623. ISSN 0028-0836. PMID 16598259. S2CID 4412156.
  14. 1 2 3 Martín-Durán, José M.; Vellutini, Bruno C.; Hejnol, Andreas (2016-12-19). "Embryonic chirality and the evolution of spiralian left–right asymmetries". Phil. Trans. R. Soc. B. 371 (1710): 20150411. doi:10.1098/rstb.2015.0411. ISSN 0962-8436. PMC 5104510. PMID 27821523.
  15. ↑ Asami, Takahiro; Cowie, Robert H.; Ohbayashi, Kako (1998-01-01). "Evolution of Mirror Images by Sexually Asymmetric Mating Behavior in Hermaphroditic Snails". The American Naturalist. 152 (2): 225–236. doi:10.1086/286163. JSTOR 10.1086/286163. PMID 18811387. S2CID 35119643.
  16. 1 2 Meshcheryakov, V. N.; Beloussov, L. V. (1975). "Asymmetrical rotations of blastomeres in early cleavage of gastropoda". Wilhelm Roux's Archives of Developmental Biology. 177 (3): 193–203. doi:10.1007/BF00848080. ISSN 0340-0794. PMID 28304794. S2CID 12448973.
  17. 1 2 Shibazaki, Yuichiro; Shimizu, Miho; Kuroda, Reiko (2004-08-24). "Body Handedness Is Directed by Genetically Determined Cytoskeletal Dynamics in the Early Embryo". Current Biology. 14 (16): 1462–1467. doi:10.1016/j.cub.2004.08.018. PMID 15324662.
  18. 1 2 Freeman, Gary; Lundelius, Judith W. (1982). "The developmental genetics of dextrality and sinistrality in the gastropodLymnaea peregra". Wilhelm Roux's Archives of Developmental Biology. 191 (2): 69–83. doi:10.1007/BF00848443. ISSN 0340-0794. PMID 28305091. S2CID 547508.
  19. ↑ Grande, Cristina; Patel, Nipam H. (2009-02-19). "Nodal signalling is involved in left–right asymmetry in snails". Nature. 457 (7232): 1007–1011. Bibcode:2009Natur.457.1007G. doi:10.1038/nature07603. ISSN 0028-0836. PMC 2661027. PMID 19098895.
  20. 1 2 Shimizu, Keisuke; Iijima, Minoru; Setiamarga, Davin HE; Sarashina, Isao; Kudoh, Tetsuhiro; Asami, Takahiro; Gittenberger, Edi; Endo, Kazuyoshi (2013-01-01). "Left-right asymmetric expression of dpp in the mantle of gastropods correlates with asymmetric shell coiling". EvoDevo. 4 (1): 15. doi:10.1186/2041-9139-4-15. ISSN 2041-9139. PMC 3680195. PMID 23711320.
  21. ↑ Kurita, Yoshihisa; Wada, Hiroshi (2011-04-27). "Evidence that gastropod torsion is driven by asymmetric cell proliferation activated by TGF-β signalling". Biology Letters. 7 (5): 759–762. doi:10.1098/rsbl.2011.0263. ISSN 1744-9561. PMC 3169068. PMID 21525052.
  22. 1 2 3 Davison, Angus; McDowell, Gary S.; Holden, Jennifer M.; Johnson, Harriet F.; Koutsovoulos, Georgios D.; Liu, M. Maureen; Hulpiau, Paco; Roy, Frans Van; Wade, Christopher M. (2016). "Formin Is Associated with Left-Right Asymmetry in the Pond Snail and the Frog". Current Biology. 26 (5): 654–660. doi:10.1016/j.cub.2015.12.071. PMC 4791482. PMID 26923788.
  23. 1 2 Kuroda, Reiko; Fujikura, Kohei; Abe, Masanori; Hosoiri, Yuji; Asakawa, Shuichi; Shimizu, Miho; Umeda, Shin; Ichikawa, Futaba; Takahashi, Hiromi (2016-10-06). "Diaphanous gene mutation affects spiral cleavage and chirality in snails". Scientific Reports. 6: 34809. Bibcode:2016NatSR...634809K. doi:10.1038/srep34809. ISSN 2045-2322. PMC 5052593. PMID 27708420.
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