Left-right asymmetry in gut development:what happens next?Sally F Burn and Robert E Hill*MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Road, Edinburgh,EH4 2XU, UKThe gastrointestinal tract is an asymmetrically patternedorgan system. The signals which initiate left-right asym-metry in the developing embryo have been extensivelystudied, but the downstream steps required to conferasymmetric morphogenesis on the gut organ primordiaare less well understood. In this paper we outline keyfindings on the tissue mechanics underlying gut asym-metry, across a range of species, and use these tosynthesise a conserved model for asymmetric gut mor-phogenesis. We also discuss the importance of correctestablishment of left-right asymmetry for gut develop-ment and the consequences of perturbations in thisprocess.IntroductionThe developing gut provides an opportunity to view anexceptional array of fundamental morphogenetic processes.Developmental phenomena such as epithelial-mesenchymalinteraction, axial patterning, cell migration, and buddingmorphogenesis are well documented. The vertebrate gastro-intestinal (GI) tract and its accessory organs initially developfrom a sheet of endoderm, which folds to form a midline tubealong the anterior-posterior (AP) axis of the embryo.(1)Following tube closure, multipotent stem cells within theendoder m differentiate and become organised into the majororgan precursors.The embryonic gut tube is progressively patterned alongthe AP axis. AP patterning of the gut endoderm is one of thefirst steps in polarising the symmetrical embryo, resulting inthe specification of regions between which morphological andgene expression differences emerge. The accessory organsof the gut (thyroid, lungs, liver and pancreas) emerge followingbudding morphogenesis of the tube along the dorsal ventralaxis.Dif ferentiation along the left-right (LR) axis provides thethird level of axial pattering and as a result the initially midlineunifor m gut tube is transformed into an asymmetric patternedsystem containing the primordia of the GI organs. A largeamount of information is known about the early stages of LRasymmetry establishment and is the subject of many excellentreviews.(2–5)The final step in establishing LR asymmetry –how organ primordia interpret asymmetric gene expressionand translate this into asymmetric morphogenesis – is lessunderstood and is the focus of this paper with respect to thegut. We discuss the importance of LR asymmetry formammalian gut development and the tissue mechanics usedto move the developing endoderm into position. We alsoexamine what happens when asymmetry is perturbed andcompare the different developmental mechanisms utilised byspecies from the animal kingdom to achieve gut asymmetry.Establishing left-right asymmetryThe journey towards the establishment of LR asymmetry canbe divided into four distinct stages.(2)The first is the breakingof symmetry and subsequent initiation of LR polarity relative tothe dorsal-ventral and AP axes. This is possibly due to nodalflow (cilia in node rotate such that a leftward flow of extra-embryonic fluid is established, potentially allowing leftwardflow of an unknown left-side determinant molecule) asillustrated in mouse embryos, though this remains conten-tious in other organisms.(6)The most recent hypothesis is thatplanar cell polarity may underlie both the ciliary andintracellular/physiological mechanisms utilised at thisstage.(7)The second stage is the transmission of LR positionalsignals from the node to lateral plate mesoderm (LPM), eitherby relay through signalling cascades or by diffusion ofmolecules, thus inducing the third stage: asymmetric geneexpression of signalling molecules in the LPM (e.g. Nodal ,Lefty2; both transiently expressed in the left LPM). Lastly isthe stage we focus on here, the initiation of asymmetric organmorphogenesis. How factors involved in this stage (e.g. Pitx2)exert control is unknown, but they may act through regulationof differential cell prolifera tion, migration and adhesion. Asummary of the four stages is provided in Fig. 1.DOI 10.1002/bies.200900056 Review articleAbbreviations: AP, anterior-posterior; ASMP, anterior splanchnic mesodermalplate; E, embryonic day; FGF, fibroblast growth factor; GI, gastrointestinal;LPM, lateral plate mesoderm; LR, left-right; SMP, splanchnic mes odermalplate.*Correspondence to: R. E. Hill, MRC Human Genetics Unit, Institute ofGenetics and Molecular Medicine, Western General Hospital, Crewe Road,Edinburgh, EH4 2XU, UK.E-mail: [email protected] 9999:1–12, ß 2009 Wiley Period icals, Inc.1Nor mal LR asymmetry is termed situs solitus; completemirror-image reversal of this arrangement is called situsinversus and is estimated to affect up to 1 in 8,000individuals.(8)Situs inversus occurs due to mutations affectingthe early stages of LR determination. Not all reversals arecomplete though and a spectrum of intermediate defects(situs ambiguus) exists, including heterotaxy (discordancebetween asymmetry of different organs), isomerism (one sideis duplicated) and isolated abnormalities in normally asym-metric organs. In contrast to the usually medically benign situsinversus, these partial reversals are of clinical importance.Heterotaxia is particularly associated with cardiac and GI tractabnormalities.One mechanism underlying heterotaxia may be localiseddisruption of LR morphogenesis affecting a subset of themechanisms utilised to establish organ placement. Hetero-taxia can be caused by mutations in single genes, andestimates of its occurrence range broadly between 1 in 6,000–20,000 live births; however, when terminations and stillbirthsare taken into consideration, the occurrence is as high as 1 in100, illustrating the importance of precise establishment of LRasymmetry for viable development.(9,10)A list of genes known to cause gut laterality defects whenmutated can be found in Table 1. The abnormal developmentof the spleen, which is characteristically a wholly left-sidedorgan, is a key indicator of heterotaxia. Spleen abnormalitiesassociated with heterotaxia mainly take the form of poly-splenia or asplenia and are usually sporadic. Familial casesoccur more rarely and mostly show autosomal recessiveinheritance.(8)Polysplenia/asplenia occurs in 1/24,000–1/40,000 live births,(10)most commonly in individuals withasymmetry defects in other organs. Spleen defects may,however, also occur
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