Abstract
Left-right patterning is among the least well understood of the three axes defining the body plan, and yet it is of no less importance, with left-right patterning defects causing structural birth defects with high morbidity and mortality, such as in complex congenital heart disease, biliary atresia, or intestinal malrotation. The cell signaling pathways that govern left-right asymmetry are highly conserved and involved multiple components of the transforming growth factor beta (TGFβ) superfamily of cell signaling molecules. Central to left-right patterning is the differential activation of Nodal on the left and bone morphogenetic protein (BMP) signaling on the right. In addition, a plethora of other cell signaling pathways including sonic hedgehog (Shh), fibroblast growth factor (FGF), and Notch also contribute to the regulation of left-right patterning. In vertebrate embryos such as the mouse, frog, or zebrafish, the specification of left-right identity requires the left-right organizer (LRO) containing cells with motile and primary cilia. Cilia-generated flow plays an important role in the left-sided propagation of Nodal signaling. Ultimately, it is the left-sided expression of the transcription factor paired-like homeodomain 2 (Pitx2) that drives visceral organ asymmetry. Interestingly, while this overall scheme for left-right patterning is well conserved evolutionarily, are striking differences that suggests caution in broadly generalizing conclusions on the molecular pathways regulating left-right patterning.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Huelsken J, Vogel R, Brinkmann V et al (2000) Requirement for beta-catenin in anterior-posterior axis formation in mice. J Cell Biol 148:567–578
Zeng L, Fagotto F, Zhang T et al (1997) The mouse Fused locus encodes Axin, an inhibitor of the Wnt signaling pathway that regulates embryonic axis formation. Cell 90:181–192
Li Y, Klena NT, Gabriel GC et al (2015) Global genetic analysis in mice unveils central role for cilia in congenital heart disease. Nature 521:520–524
Ware SM, Jefferies JL (2012) New genetic insights into congenital heart disease. J Clin Exp Cardiolog S8:003
Mack CL, Sokol RJ (2005) Unraveling the pathogenesis and etiology of biliary atresia. Pediatr Res 57:87R–94R
Martin V, Shaw-Smith C (2010) Review of genetic factors in intestinal malrotation. Pediatr Surg Int 26:769–781
Zhang Z, Alpert D, Francis R et al (2009) Massively parallel sequencing identifies the gene Megf8 with ENU-induced mutation causing heterotaxy. Proc Natl Acad Sci U S A 106:3219–3224
Yamamoto M, Meno C, Sakai Y et al (2001) The transcription factor FoxH1 (FAST) mediates Nodal signaling during anterior-posterior patterning and node formation in the mouse. Genes Dev 15:1242–1256
Saijoh Y, Adachi H, Sakuma R et al (2000) Left-right asymmetric expression of lefty2 and nodal is induced by a signaling pathway that includes the transcription factor FAST2. Mol Cell 5:35–47
Osada SI, Saijoh Y, Frisch A et al (2000) Activin/nodal responsiveness and asymmetric expression of a Xenopus nodal-related gene converge on a FAST-regulated module in intron 1. Development 127:2503–2514
Krebs LT, Iwai N, Nonaka S et al (2003) Notch signaling regulates left-right asymmetry determination by inducing Nodal expression. Genes Dev 17:1207–1212
Rankin CT, Bunton T, Lawler AM et al (2000) Regulation of left-right patterning in mice by growth/differentiation factor-1. Nat Genet 24:262–265
Inacio JM, Marques S, Nakamura T et al (2013) The dynamic right-to-left translocation of Cerl2 is involved in the regulation and termination of Nodal activity in the mouse node. PLoS One 8, e60406
Mine N, Anderson RM, Klingensmith J (2008) BMP antagonism is required in both the node and lateral plate mesoderm for mammalian left-right axis establishment. Development 135:2425–2434
Veerkamp J, Rudolph F, Cseresnyes Z et al (2013) Unilateral dampening of Bmp activity by nodal generates cardiac left-right asymmetry. Dev Cell 24:660–667
Oh SP, Li E (1997) The signaling pathway mediated by the type IIB activin receptor controls axial patterning and lateral asymmetry in the mouse. Genes Dev 11:1812–1826
Kishigami S, Yoshikawa S, Castranio T et al (2004) BMP signaling through ACVRI is required for left-right patterning in the early mouse embryo. Dev Biol 276:185–193
Tam PP, Behringer RR (1997) Mouse gastrulation: the formation of a mammalian body plan. Mech Dev 68:3–25
Nonaka S, Tanaka Y, Okada Y et al (1998) Randomization of left-right asymmetry due to loss of nodal cilia generating leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein. Cell 95:829–837
Takeda S, Yonekawa Y, Tanaka Y et al (1999) Left-right asymmetry and kinesin superfamily protein KIF3A: new insights in determination of laterality and mesoderm induction by kif3A−/− mice analysis. J Cell Biol 145:825–836
Afzelius BA (1976) A human syndrome caused by immotile cilia. Science 193:317–319
Supp DM, Witte DP, Potter SS et al (1997) Mutation of an axonemal dynein affects left-right asymmetry in inversus viscerum mice. Nature 389:963–966
Tan SY, Rosenthal J, Zhao XQ et al (2007) Heterotaxy and complex structural heart defects in a mutant mouse model of primary ciliary dyskinesia. J Clin Invest 117:3742–3752
Hornef N, Olbrich H, Horvath J et al (2006) DNAH5 mutations are a common cause of primary ciliary dyskinesia with outer dynein arm defects. Am J Respir Crit Care Med 174:120–126
Nakhleh N, Francis R, Giese RA et al (2012) High prevalence of respiratory ciliary dysfunction in congenital heart disease patients with heterotaxy. Circulation 125:2232–2242
Zariwala M, Noone PG, Sannuti A et al (2001) Germline mutations in an intermediate chain dynein cause primary ciliary dyskinesia. Am J Respir Cell Mol Biol 25:577–583
Yu X, Ng CP, Habacher H et al (2008) Foxj1 transcription factors are master regulators of the motile ciliogenic program. Nat Genet 40:1445–1453
Chen J, Knowles HJ, Hebert JL et al (1998) Mutation of the mouse hepatocyte nuclear factor/forkhead homologue 4 gene results in an absence of cilia and random left-right asymmetry. J Clin Invest 102:1077–1082
Brody SL, Yan XH, Wuerffel MK et al (2000) Ciliogenesis and left-right axis defects in forkhead factor HFH-4-null mice. Am J Respir Cell Mol Biol 23:45–51
Stubbs JL, Oishi I, Izpisua Belmonte JC et al (2008) The forkhead protein Foxj1 specifies node-like cilia in Xenopus and zebrafish embryos. Nat Genet 40:1454–1460
Tanaka Y, Okada Y, Hirokawa N (2005) FGF-induced vesicular release of Sonic hedgehog and retinoic acid in leftward nodal flow is critical for left-right determination. Nature 435:172–177
Levin M, Pagan S, Roberts DJ et al (1997) Left/right patterning signals and the independent regulation of different aspects of situs in the chick embryo. Dev Biol 189:57–67
Kawakami Y, Raya A, Raya RM et al (2005) Retinoic acid signalling links left-right asymmetric patterning and bilaterally symmetric somitogenesis in the zebrafish embryo. Nature 435:165–171
Pennekamp P, Karcher C, Fischer A et al (2002) The ion channel polycystin-2 is required for left-right axis determination in mice. Curr Biol 12:938–943
McGrath J, Somlo S, Makova S et al (2003) Two populations of node monocilia initiate left-right asymmetry in the mouse. Cell 114:61–73
Karcher C, Fischer A, Schweickert A et al (2005) Lack of a laterality phenotype in Pkd1 knock-out embryos correlates with absence of polycystin-1 in nodal cilia. Differentiation 73:425–432
Field S, Riley KL, Grimes DT et al (2011) Pkd1l1 establishes left-right asymmetry and physically interacts with Pkd2. Development 138:1131–1142
Kamura K, Kobayashi D, Uehara Y et al (2011) Pkd1l1 complexes with Pkd2 on motile cilia and functions to establish the left-right axis. Development 138:1121–1129
Piedra ME, Icardo JM, Albajar M et al (1998) Pitx2 participates in the late phase of the pathway controlling left-right asymmetry. Cell 94:319–324
Ai D, Liu W, Ma L et al (2006) Pitx2 regulates cardiac left-right asymmetry by patterning second cardiac lineage-derived myocardium. Dev Biol 296:437–449
Noel ES, Verhoeven M, Lagendijk AK et al (2013) A Nodal-independent and tissue-intrinsic mechanism controls heart-looping chirality. Nat Commun 4:2754
Major RJ, Irvine KD (2006) Localization and requirement for Myosin II at the dorsal-ventral compartment boundary of the Drosophila wing. Dev Dyn 235:3051–3058
Davis NM, Kurpios NA, Sun X et al (2008) The chirality of gut rotation derives from left-right asymmetric changes in the architecture of the dorsal mesentery. Dev Cell 15:134–145
Welsh IC, Thomsen M, Gludish DW et al (2013) Integration of left-right Pitx2 transcription and Wnt signaling drives asymmetric gut morphogenesis via Daam2. Dev Cell 26:629–644
Gage PJ, Suh H, Camper SA (1999) Dosage requirement of Pitx2 for development of multiple organs. Development 126:4643–4651
Kitamura K, Miura H, Miyagawa-Tomita S et al (1999) Mouse Pitx2 deficiency leads to anomalies of the ventral body wall, heart, extra- and periocular mesoderm and right pulmonary isomerism. Development 126:5749–5758
Liu S, Cheung E, Rajopadhye M et al (2001) Isomerism and solution dynamics of (90)Y-labeled DTPA – biomolecule conjugates. Bioconjug Chem 12:84–91
Fischer A, Viebahn C, Blum M (2002) FGF8 acts as a right determinant during establishment of the left-right axis in the rabbit. Curr Biol 12:1807–1816
Concha ML, Wilson SW (2001) Asymmetry in the epithalamus of vertebrates. J Anat 199:63–84
Long S, Ahmad N, Rebagliati M (2003) The zebrafish nodal-related gene southpaw is required for visceral and diencephalic left-right asymmetry. Development 130:2303–2316
Kennedy DN, O’Craven KM, Ticho BS et al (1999) Structural and functional brain asymmetries in human situs inversus totalis. Neurology 53:1260–1265
Gros J, Feistel K, Viebahn C et al (2009) Cell movements at Hensen’s node establish left/right asymmetric gene expression in the chick. Science 324:941–944
Rodriguez Esteban C, Capdevila J et al (1999) The novel Cer-like protein Caronte mediates the establishment of embryonic left-right asymmetry. Nature 401:243–251
Aw S, Adams DS, Qiu D et al (2008) H, K-ATPase protein localization and Kir4.1 function reveal concordance of three axes during early determination of left-right asymmetry. Mech Dev 125:353–372
Adams DS, Robinson KR, Fukumoto T et al (2006) Early, H+-V-ATPase-dependent proton flux is necessary for consistent left-right patterning of non-mammalian vertebrates. Development 133:1657–1671
Fukumoto T, Kema IP, Levin M (2005) Serotonin signaling is a very early step in patterning of the left-right axis in chick and frog embryos. Curr Biol 15:794–803
Acknowledgement
This work is supported by funding from NIH HL098180.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2016 Springer-Verlag Wien
About this chapter
Cite this chapter
Klena, N.T., Gabriel, G.C., Lo, C.W. (2016). Molecular Pathways and Animal Models of Defects of Situs. In: Rickert-Sperling, S., Kelly, R., Driscoll, D. (eds) Congenital Heart Diseases: The Broken Heart. Springer, Vienna. https://doi.org/10.1007/978-3-7091-1883-2_39
Download citation
DOI: https://doi.org/10.1007/978-3-7091-1883-2_39
Publisher Name: Springer, Vienna
Print ISBN: 978-3-7091-1882-5
Online ISBN: 978-3-7091-1883-2
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)