DOI 10 1002 bies 200900056 Review article 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 UK The gastrointestinal tract is an asymmetrically patterned organ system The signals which initiate left right asymmetry in the developing embryo have been extensively studied but the downstream steps required to confer asymmetric morphogenesis on the gut organ primordia are less well understood In this paper we outline key findings on the tissue mechanics underlying gut asymmetry across a range of species and use these to synthesise a conserved model for asymmetric gut morphogenesis We also discuss the importance of correct establishment of left right asymmetry for gut development and the consequences of perturbations in this process Introduction The developing gut provides an opportunity to view an exceptional array of fundamental morphogenetic processes Developmental phenomena such as epithelial mesenchymal interaction axial patterning cell migration and budding morphogenesis are well documented The vertebrate gastrointestinal GI tract and its accessory organs initially develop from a sheet of endoderm which folds to form a midline tube along the anterior posterior AP axis of the embryo 1 Following tube closure multipotent stem cells within the endoderm differentiate and become organised into the major organ precursors The embryonic gut tube is progressively patterned along the AP axis AP patterning of the gut endoderm is one of the first steps in polarising the symmetrical embryo resulting in the specification of regions between which morphological and gene expression differences emerge The accessory organs of the gut thyroid lungs liver and pancreas emerge following budding morphogenesis of the tube along the dorsal ventral axis Abbreviations AP anterior posterior ASMP anterior splanchnic mesodermal plate E embryonic day FGF fibroblast growth factor GI gastrointestinal LPM lateral plate mesoderm LR left right SMP splanchnic mesodermal plate Correspondence to R E Hill MRC Human Genetics Unit Institute of Genetics and Molecular Medicine Western General Hospital Crewe Road Edinburgh EH4 2XU UK E mail bob hill hgu mrc ac uk BioEssays 9999 1 12 2009 Wiley Periodicals Inc Differentiation along the left right LR axis provides the third level of axial pattering and as a result the initially midline uniform gut tube is transformed into an asymmetric patterned system containing the primordia of the GI organs A large amount of information is known about the early stages of LR asymmetry establishment and is the subject of many excellent reviews 2 5 The final step in establishing LR asymmetry how organ primordia interpret asymmetric gene expression and translate this into asymmetric morphogenesis is less understood and is the focus of this paper with respect to the gut We discuss the importance of LR asymmetry for mammalian gut development and the tissue mechanics used to move the developing endoderm into position We also examine what happens when asymmetry is perturbed and compare the different developmental mechanisms utilised by species from the animal kingdom to achieve gut asymmetry Establishing left right asymmetry The journey towards the establishment of LR asymmetry can be divided into four distinct stages 2 The first is the breaking of symmetry and subsequent initiation of LR polarity relative to the dorsal ventral and AP axes This is possibly due to nodal flow cilia in node rotate such that a leftward flow of extraembryonic fluid is established potentially allowing leftward flow of an unknown left side determinant molecule as illustrated in mouse embryos though this remains contentious in other organisms 6 The most recent hypothesis is that planar cell polarity may underlie both the ciliary and intracellular physiological mechanisms utilised at this stage 7 The second stage is the transmission of LR positional signals from the node to lateral plate mesoderm LPM either by relay through signalling cascades or by diffusion of molecules thus inducing the third stage asymmetric gene expression of signalling molecules in the LPM e g Nodal Lefty2 both transiently expressed in the left LPM Lastly is the stage we focus on here the initiation of asymmetric organ morphogenesis How factors involved in this stage e g Pitx2 exert control is unknown but they may act through regulation of differential cell proliferation migration and adhesion A summary of the four stages is provided in Fig 1 1 Review article Figure 1 Genetic pathway for establishment of gut LR asymmetry in the mouse The determination of LR asymmetry can be divided into four stages breaking of symmetry blue box transfer of LR signals from the node to LPM pink box LR asymmetric expression in the LPM orange box and situs specific LR asymmetric morphogenesis yellow box Genes involved in node formation are written in light blue genes for cilia assembly function are in red midline genes are written in green genes involved in the amplification of LR asymmetric information within the LPM are written in purple genes required for situs specific morphogenesis are dark blue The pathway depicted is based on events in mouse The initial symmetry breaking event in this species involves formation of the node and subsequent nodal flow however this is not the case in many other species A diversity of mechanisms is employed to break symmetry across the animal kingdom a number of in depth reviews are available on this subject 6 51 52 Homology can however be detected in the more downstream events such as transfer amplification and situs specific interpretation of LR asymmetric information Normal LR asymmetry is termed situs solitus complete mirror image reversal of this arrangement is called situs inversus and is estimated to affect up to 1 in 8 000 individuals 8 Situs inversus occurs due to mutations affecting the early stages of LR determination Not all reversals are complete though and a spectrum of intermediate defects situs ambiguus exists including heterotaxy discordance between asymmetry of different organs isomerism one side is duplicated and isolated abnormalities in normally asymmetric organs In contrast to the usually medically benign situs inversus these partial reversals are of clinical importance Heterotaxia is particularly associated with cardiac and GI tract abnormalities 2 S F
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