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Asymmetry Inside the Symmetry: Mechanisms and Disorders of Laterality

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Asymmetry Inside the Symmetry: Mechanisms and Disorders of Laterality Asymmetry Inside The Symmetry: Mechanisms and Disorders Of Laterality Yasemin ALANAY1, Ersin GÜMÜŞ2, Miray SEKKİN2, Sebile GÜLER2, A. Nur ÇAKAR3 Ankara-Turkey Asy mmetry of the left-right (L-R) axis is a feature of vertebrates that is apparent in the viscera and vas- culature. An understanding of L-R patterning in human development is aided by familiarity with key ev ents and important pathways in mammalian embryogenesis.The induction of L-R asymmetry follows the establishment of the anteroposterior (A-P or rostrocaudal) and dorsoventral (D-V) axes and re- quires the pre-existing midline symmetry to be broken before sidedness is induced via a series of complex, coordinated molecular signaling events. In this review, our aim is to describe the molecular background of this embryological process, and giv e brief knowledge concerning its clinical conse- quences. (Gynecol Obstet Reprod Med 2006; 12:000-000) Key Words: Heterotaxy, Laterality, Situs anomalies Many living creatures in nature, from Ascidians to man, T here are also many l ess defin ed asymmetries that hav e exhibit symmetry which can be described as correspondence been the focus of many studies to date. Human hand prefe- in size, shape and relative position of congruent components rence and the functional asymmetry of the brain hemispheres are still attractive research areas, and the basics of genetic about a plane or axis, as a feature of their external body plan. 1 Most animals possess symmetrical body plans such as; sphe- mechanisms are still controversial. Cell mediated immune 2 rical, radial, chiral, bilateral and pseudo-bilateral. In har- hypersensitivity is stronger on the left side of the body and mony with this, possession of a symmetrical body plan is the left side of the scrotum descends lower than the right in 3 one of the conspicuous morphological characteristics of ver- correlation with handedness. In addition, it has already been pointed out that non-visceral asymmetries exhibit an interes- tebrates. Despite this symmetry in morphology, vertebrates 4,5 also exhibit strikingly invariant left-right asymmetry of vis- ting relationship with gender. Data obtained from human 6,7 ceral organs. In the thorax, the cardiac apex points to the left hermaphrodites is likely to support this relationship. and the aorta arches to the left. In the abdomen, while the li- Interesting information in this area of research is provided ver and gallbladder are on the right, the stomach and spleen by the fact that non-conjoined monozygotic twins exhibit op- are situated on the left. Moreover, the blood vessels also ex- posite directionality of markers such as hand preference, hair hibit apparent asymmetric development. Besides the asym- whorl direction, tooth patterns, unilateral eye and ear defects, metric development of these impaired organs, asymmetric cleft lip, cleft palate, supernumerary teeth and even tu mor lo- development, morphology, placement and even physiology cations and undescended testicles without exhibiting any vis- of paired organs such as the lungs (the right lung consists of 8 ceral laterality defects that characterize conjoined twins. three lobes while the left has only two), kidneys and brain hemispheres also contribute to asymmetry. In summary, although human beings seem to be bilateral- ly symmetric, they possess a strikingly invariant asymmetry Asymmetry in Humans beneath this symmetry that can be called “ pseudo-bilateral” In human beings, possessing an asymmetrical internal symmetry. Asymmetry, here, in fact is not only anatomic or architecture is not the only eviden ce o f existing asymmetry. morphologic but also functional and even physiologic. De- viations from normal development of left right asymmetry 1Clinical Genetics Unit, Department of Pediatrics, Hacettepe University can lead to numerous defects with significant clinical impli- Faculty of Medicine, 2Medical Student, Hacettepe University Faculty of cations such as bilateral symmetry (lack of asymmetry in or- 3 Medicine, Department of Histology and Embryology, Hacettepe Univer- gan physiology), isomerism (duplication of left or right si- sity Faculty of Medicine, Ankara, TURKEY ded paired organs), heterotaxy or situs ambiguous (randomi- Address of Correspondence Yasemin Alanay zation of placement of organs like the heart), situs inversus Clinical Genetics Unit (reversal of a particular organ’s orientation), situs inversus 9 totalis (total left right mirror image inversion of organs). Department of Pediatrics Hacettepe University It is important to understand all aspects of left right Faculty of Medicine asymmetry generating mechanisms in order to explain cau- ses of thes e defects at the molecular lev el and clari fy no rmal Ankara, TURKEY development of embryos. Three orthogonal axes are major Submitted for Publication: 01.03.2006 references in embryological development; dorsal-ventral Accepted for Publication: 20.03.2006 (DV), anterior-posterior (AP) and left-right (LR) ax es. DV 70 Gynecology Obstetric & Reproductive Medicine 2006; 12:70-78 71 and AP axes have been well defined, but our knowledge o f the molecular cascades that play a role in the development of LR asymmetry is still limited and this study area is full of left right asymmetry? These and more questions will find their unanswered questions. answers when molecular, genetic and biochemical levels of embryo asymmetry development are understood. Up to the first molecular studies used to clari fy th e mec- hanisms playing a role in assembling left right asymmetry The aim of this review is to summarize the presently de- during embryological development, drugs that produce de- fined molecular structures, signal pathways and models exp- fects in left right asymmetric manner or randomize asymmet- laining ciliary and node function and the related clinical ry were used for the same aim.10 The greatest contribution to problems commonly seen. this field of research was obtained by molecular studies on many species including both invertebrates and vertebrates. Pathway to Asymmetry : the NODE By now, with studies executed at the molecular level, many Embryonic axes start to be set invisibly very early. First- endogen molecules thought to be related to LR asymmetry ly, the anteroposterior axis is defined by the second polar have been found and, via these endogen molecules, possible body (which refers to anterior) then the dorsoventral axis is mechanisms and models have been suggested for LR asym- defined by the inner cell mass of blastocyst (which refers to metry establishment. Besides providing valuable information dorsal) and trophoblast (which refers to ventral) opposite to about LR asymmetry generating mechanisms, these studies it. After these axes are set, right-left axis occurs spontane- also help us understand the evolutionary process of asym- ously. The appearan ce o f symmetry is seen during the for- metry and conservation of mechanisms between species. mation of the primitive streak which is made up of the epib- last cells moving from caudal to cranial area at gastrulation From the molecular point of view the establishment o f rd LR asymmetry can be divided into four steps: 1) Initial brea- (3 week). Chordin, nodal, cripto and Vg1 are major signal- king of LR symmetry in or near the node (Hensen’s node) ling molecules for formation of the primitive streak and are 16 with respect to the DV and AP axes. 2) T rans fer o f LR active in the caudal area of the axis. At the anterior end o f asymmetric signals from the node to the lateral plate meso- the primitive streak, the primitive node develops where the derm. 3) LR asymmetric expression of signaling molecules cells delaminate to form the mesoderm. Detailed studies in (asymmetric gene expression). 4) LR asymmetric morphoge- mice models have demonstrated that the mouse node (or or- nesis of the visceral organs that are induced by these signa- ganizer) for asymmetry exposes at the time of gastrulation in ling molecules.11-14 a region at the distal tip of the embryo where dorsal ectoder- mal and ventral endodermal cells each with a simple cilia are The process resulting in asymmetric gene expression, step in contact, separated only by a basement membrane and 1, is noteworthy as it is the initiation part of established when a node is grafted to an ectopic side, the host is induced asymmetry. The question: “What determines the sidedness of for a second body axis.17,18,19 When the primitive streak reg- the first gene that is asymmetrically expressed?” is the center resses, the node moves towards the posterior end of the of attention. Syndecans, adhesion junctions, gap junctions, embryo, and ingresses after somitogenesis. Firstly the prec- ion fluxes, intracellular motor proteins and cilia models are hordal plate, then the notochord are formed after gastrulation shown to be parts of mechanisms previous to asymmetric ge- 17 ,20 15 by the cells invading throughout the node. ne expression. Another important part of the LR asymmet- The notochord ric development is step 4, in other words asymmetric estab- is considered to be the primitive axis of the very early embr- lishment of the viscera. Transfer of asymmetric signals (step yo.19 After the formation of the notochord, the embryo 2) and asymmetric gene expressions (step 3) such as transfor- shows bilateral symmetry for some time. At initiation of ming growth factor-β related factors, Nodal and Lefty-2 re- functioning of node cells, asymmetry inside the symmetry sult in asymmetric morphogenesis. During this process Nodal starts to be generated. (figure 1) acts as a left side det erminant, whereas L efty-2 is an an tago- Each node cell carries a monocilium and all monocilia nist that restricts the duration and the site of Nodal action.13 are very closely placed. 17 An important question arises about At least three different patterns can be distinguished for step monocilia; whether node monocilia were functional or not. 4; 1) directional looping of a tube (e.g.
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