Mechanisms of Left–Right Determination in Vertebrates
2000; Cell Press; Volume: 101; Issue: 1 Linguagem: Inglês
10.1016/s0092-8674(00)80619-4
ISSN1097-4172
AutoresJavier Capdevila, Kyle Vogan, Clifford J. Tabin, Juan Carlos Izpisúa Belmonte,
Tópico(s)Paleontology and Evolutionary Biology
ResumoDuring embryogenesis, an important manifestation of the emerging complexity of the vertebrate body plan is the appearance of a third axis of asymmetry, the left–right axis (L/R). Asymmetries along the L/R axis are readily apparent in the adult, where internal organs such as the heart, stomach, and intestines all have a characteristic asymmetric structure and are asymmetrically positioned within the body cavity (Figure 1). Embryonic primordia give rise to these and other organs during development by following complex patterns of loops and turns that result in the stereotyped positioning of organs (reviewed by 22Fujinaga M Development of sidedness of asymmetric body structures in vertebrates.Int. J. Dev. Biol. 1997; 41: 153-186PubMed Google Scholar). Remarkably, the direction of these loops and turns and the relative positioning of organs within the body cavity appear to be conserved in all vertebrates, suggesting that this asymmetric structure and arrangement of organs is required for their normal function. For example, the heart has to be asymmetric to pump blood efficiently, and asymmetric development of the digestive system (which is particularly complex in vertebrates) allows it to be packed more efficiently within the body cavity. Thus, the normal disposition of organs, called situs solitus (Figure 1A), is an essential and distinctive feature of the vertebrate body plan. From an evolutionary perspective, the progression from bilateral symmetry to global, handed asymmetry required that important changes be made on at least three distinct levels of organization. These could have arisen in three sequential steps, although other equally plausible evolutionary scenarios can also be envisioned. The first step—the evolution of individual organ asymmetries—would have provided an initial level of complexity over the ancestral state of simple bilateral symmetry. The next step—the development of globally coordinated asymmetry—would have required the evolution of an additional level of regulation to ensure that all of the developing organ systems adopted consistent L/R orientations relative to each other. The final stage—characterized by global, handed asymmetry—would have required the innovation of an initial biasing mechanism to consistently orient the L/R axis with reference to the other two primary axes of the body. Developmentally, the failure to properly pattern the L/R axis at any of these three levels of organization results in distinct classes of laterality defects. The first, known as isomerism (Figure 1B and Figure 1C), results from a failure to achieve L/R asymmetry at the level of individual organs (examples include left and right atrial isomerisms, left and right pulmonary isomerisms, midline liver, etc.). A second condition, known as heterotaxia, describes a situation where one or more of the individual organ systems develops with reversed L/R polarity (i.e., right-sided stomach, left-sided liver, intestinal malrotation, etc.), and results from a failure to properly coordinate the asymmetric development of multiple organ systems. Finally, the failure to properly align the L/R axis with the other two body axes produces a condition known as situs inversus, characterized by a complete inversion of the global L/R axis (Figure 1D, compare with 1A). The mechanisms underlying L/R determination have fascinated biologists for decades, but not until recently have researchers been able to link specific gene functions to particular processes during the development of the L/R axis. The existence of mouse and zebrafish mutants, and inherited human syndromes with distinct laterality defects, had suggested that the process of L/R determination is under genetic control. This expectation has been confirmed by the recent identification of several genes that display striking, side-specific patterns of expression in the early embryo. Surgical manipulations in chick and frog embryos have further helped to define the roles that specific embryonic structures play during the process of L/R determination. In this review, we examine recent discoveries that have deepened our understanding of the mechanisms that direct the development of the L/R axis. We have subdivided the process of L/R determination into four stages: (1) the initial breaking of symmetry, which leads to the establishment of specific patterns of gene expression in and around the embryonic organizer; (2) the relay of L/R positional information from the organizer to the lateral plate mesoderm (LPM); (3) the stabilization of broad domains of side-specific gene expression, and; (4) the transfer of L/R information to the organ primordia, and the elaboration of specific programs of asymmetric morphogenesis. Conceptually, perhaps the most challenging question in the field of L/R asymmetry is to understand how the early bilateral symmetry of the embryo is broken such that the L/R axis becomes consistently oriented with respect to the anteroposterior (A/P) and dorsoventral (D/V) axes, the other two primary axes of the embryo. To achieve this end, the embryo must integrate information concerning the relative orientations of the A/P and D/V axes, which are established at an earlier stage in development, and use this information to produce an initial difference or "bias" between cells on either side of the embryonic midline. While various theoretical models have been put forward to explain how this initial symmetry-breaking event might occur (see, for instance, 7Brown N.A Wolpert L The development of handedness in left/right asymmetry.Development. 1990; 127: 1081-1093Google Scholar and 40Levin M Mercola M The compulsion of chirality toward an understanding of left-right asymmetry .Genes Dev. 1998; 12 (a): 763-769Crossref PubMed Scopus (91) Google Scholar), there is little empirical evidence supporting any of the proposed models, and so the true mechanisms underlying the symmetry-breaking process have remained surprisingly difficult to elucidate. A series of elegant studies in mouse (60Nonaka S Tanaka Y Okada Y Takeda S Harada A Kanai Y Kido M Hirokawa N Randomization of left-right asymmetry due to loss of nodal cilia generating leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein.Cell. 1998; 95: 829-837Abstract Full Text Full Text PDF PubMed Scopus (1175) Google Scholar, 64Okada Y Nonaka S Tanaka Y Saijoh Y Hamada H Hirokawa N Abnormal nodal flow precedes situs inversus in iv and inv mice.Mol. Cell. 1999; 4: 459-468Abstract Full Text Full Text PDF PubMed Scopus (351) Google Scholar, 88Takeda S Yonekawa Y Tanaka Y Okada Y Nonaka S Hirokawa N Left-right asymmetry and kinesin superfamily protein KIF3A new insights in determination of laterality and mesoderm induction by kif3A−/− mice analysis .J. Cell Biol. 1999; 145: 825-836Crossref PubMed Scopus (365) Google Scholar) have recently provided us with the first experimentally deduced model of L/R axis determination in vertebrates. Interestingly, this model is entirely consistent with a previously observed correlation between situs abnormalities and ciliary dysfunction in humans (2Afzelius B.A A human syndrome caused by immotile cilia.Science. 1976; 193: 317-319Crossref PubMed Scopus (889) Google Scholar). The breakthrough came from analyzing a specialized cluster of monocilia present on the ventral surface of the mouse node, the mammalian equivalent of the early embryonic organizer region identified through classical transplantation studies in Xenopus. These monocilia, which project into the extraembryonic space surrounding the egg cylinder, exhibit a novel type of vortical motion that generates an apparent leftward flow of extraembryonic fluid in the node region (60Nonaka S Tanaka Y Okada Y Takeda S Harada A Kanai Y Kido M Hirokawa N Randomization of left-right asymmetry due to loss of nodal cilia generating leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein.Cell. 1998; 95: 829-837Abstract Full Text Full Text PDF PubMed Scopus (1175) Google Scholar, 64Okada Y Nonaka S Tanaka Y Saijoh Y Hamada H Hirokawa N Abnormal nodal flow precedes situs inversus in iv and inv mice.Mol. Cell. 1999; 4: 459-468Abstract Full Text Full Text PDF PubMed Scopus (351) Google Scholar, 88Takeda S Yonekawa Y Tanaka Y Okada Y Nonaka S Hirokawa N Left-right asymmetry and kinesin superfamily protein KIF3A new insights in determination of laterality and mesoderm induction by kif3A−/− mice analysis .J. Cell Biol. 1999; 145: 825-836Crossref PubMed Scopus (365) Google Scholar). This so-called "nodal flow" has been proposed to function as the initiating event in the formation of the L/R axis by causing an initial L/R difference in the relative distribution of one or more extracellular inducers (Figure 2A), thus triggering the activation of distinct signaling pathways on the left and right sides of the embryo (reviewed by 94Vogan K.J Tabin C.J A new spin on handed asymmetry.Nature. 1999; 397: 295-298Crossref PubMed Scopus (43) Google Scholar and 87Supp D.M Potter S Brueckner M Molecular motors the driving force behind mammalian left-right development .Trend Cell Biol. 2000; 10: 41-45Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar). Strong support for the cilia model comes from studies of the inversus viscerum (iv) mouse, a classical mutant strain with a near random incidence of situs solitus and situs inversus. The product of the iv locus, called left–right dynein (Lrd), is an axonemal-type dynein heavy chain molecule expressed in the ventral node cells and other cell types in the embryo (85Supp D.M Witte D.P Potter S.S Brueckner M Mutation of an axonemal dynein affects left-right asymmetry in inversus viscerum mice.Nature. 1997; 389: 963-966Crossref PubMed Scopus (437) Google Scholar, 86Supp D.M Brueckner M Kuehn M.R Witte D.P Lowe L.A McGrath J Corrales J Potter S.S Targeted deletion of the ATP binding domain of left-right dynein confirms its role in specifying development of left-right asymmetries.Development. 1999; 126: 5495-5504PubMed Google Scholar; see also references therein). In keeping with the presumed function of this molecule as a critical force-generating component of the ciliary motor, mice lacking a functional Lrd have immotile nodal cilia (64Okada Y Nonaka S Tanaka Y Saijoh Y Hamada H Hirokawa N Abnormal nodal flow precedes situs inversus in iv and inv mice.Mol. Cell. 1999; 4: 459-468Abstract Full Text Full Text PDF PubMed Scopus (351) Google Scholar, 86Supp D.M Brueckner M Kuehn M.R Witte D.P Lowe L.A McGrath J Corrales J Potter S.S Targeted deletion of the ATP binding domain of left-right dynein confirms its role in specifying development of left-right asymmetries.Development. 1999; 126: 5495-5504PubMed Google Scholar) and thus fail to produce any nodal flow (64Okada Y Nonaka S Tanaka Y Saijoh Y Hamada H Hirokawa N Abnormal nodal flow precedes situs inversus in iv and inv mice.Mol. Cell. 1999; 4: 459-468Abstract Full Text Full Text PDF PubMed Scopus (351) Google Scholar). Mice deficient for either KIF3A (51Marszalek J.R Ruiz-Lozano P Roberts E Chien K.R Goldstein L.S Situs inversus and embryonic ciliary morphogenesis defects in mouse mutants lacking the KIF3A subunit of kinesin-II.Proc. Natl. Acad. Sci. USA. 1999; 96: 5043-5048Crossref PubMed Scopus (424) Google Scholar, 88Takeda S Yonekawa Y Tanaka Y Okada Y Nonaka S Hirokawa N Left-right asymmetry and kinesin superfamily protein KIF3A new insights in determination of laterality and mesoderm induction by kif3A−/− mice analysis .J. Cell Biol. 1999; 145: 825-836Crossref PubMed Scopus (365) Google Scholar) or KIF3B (60Nonaka S Tanaka Y Okada Y Takeda S Harada A Kanai Y Kido M Hirokawa N Randomization of left-right asymmetry due to loss of nodal cilia generating leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein.Cell. 1998; 95: 829-837Abstract Full Text Full Text PDF PubMed Scopus (1175) Google Scholar), two kinesin molecules required for the assembly of nodal cilia, likewise show complex situs defects. By contrast, studies carried out with the inv mouse, the only well-established murine model of situs inversus (101Yokoyama T Copeland N.G Jenkins N.A Montgomery C.A Elder F.F Overbeek P.A Reversal of left-right asymmetry a situs inversus mutation .Science. 1993; 260: 679-682Crossref PubMed Scopus (354) Google Scholar), are not as easy to reconcile with the simple morphogen flow model described above. The difficulty lies in the observation that, despite the fact that nearly all inv mutants develop with a completely reversed L/R axis, the direction of nodal flow is not altered in these mice, although the flow is weaker than in wild-type controls (64Okada Y Nonaka S Tanaka Y Saijoh Y Hamada H Hirokawa N Abnormal nodal flow precedes situs inversus in iv and inv mice.Mol. Cell. 1999; 4: 459-468Abstract Full Text Full Text PDF PubMed Scopus (351) Google Scholar). On the surface, these findings would seem to argue against the nodal flow hypothesis, since it is not clear how a properly oriented (albeit reduced) nodal flow could result in a consistent inversion of the L/R axis. However, one way of solving this dilemma is to assume that the inv gene product does not act at the level of the biasing mechanism per se, but instead, acts downstream in the initial interpretation of early L/R signaling cues. In this scenario, the reduction in nodal flow (possibly a pleiotropic effect of the inv mutation) might help to explain the less than 100% incidence of situs inversus seen in these mice. Other models have also been proposed (64Okada Y Nonaka S Tanaka Y Saijoh Y Hamada H Hirokawa N Abnormal nodal flow precedes situs inversus in iv and inv mice.Mol. 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For instance, a transient morphological asymmetry is apparent at the chick node as early as stage 4 (17Cooke J Vertebrate embryo handedness.Nature. 1995; 374: 681Crossref PubMed Scopus (38) Google Scholar). Likewise, a number of genes are expressed asymmetrically at the chick node beginning at stage 5, including Sonic hedgehog (Shh), which becomes restricted to left side by an inferred Activin-like activity (43Levin M Johnson R.L Stern C.D Kuehn M Tabin C A molecular pathway determining left-right asymmetry in chick embryogenesis.Cell. 1995; 82: 803-814Abstract Full Text PDF PubMed Scopus (635) Google Scholar), and Fgf-8, which is expressed only on the right (4Boettger T Wittler L Kessel M FGF8 functions in the specification of the right body side of the chick.Curr. Biol. 1999; 9: 277-280Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar). The fact that these early asymmetries in chick are all centered at the node strongly implies that this is the site where L/R patterning information first originates in the chick, and argues that the underlying mechanism of symmetry-breaking might be similar between mouse and chick. Despite these arguments in favor of a conserved mechanism of symmetry-breaking, there are a number of significant differences between mouse and chick with respect to both the timing of early L/R patterning events and the way specific genes are deployed during the initial stages of L/R axis formation. In chick, for instance, Shh is expressed asymmetrically and plays a central role in the transfer of left-sided positional information from the node to the LPM (43Levin M Johnson R.L Stern C.D Kuehn M Tabin C A molecular pathway determining left-right asymmetry in chick embryogenesis.Cell. 1995; 82: 803-814Abstract Full Text PDF PubMed Scopus (635) Google Scholar, 65Pagán-Westphal S.M Tabin C.J The transfer of left-right positional information during chick embryogenesis.Cell. 1998; 93: 25-35Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar). Similarly, asymmetric expression of Fgf-8 at the chick node is required to prevent the left-sided pathway from becoming inappropriately activated on the right side (4Boettger T Wittler L Kessel M FGF8 functions in the specification of the right body side of the chick.Curr. Biol. 1999; 9: 277-280Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar). 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Natl. Acad. Sci. USA. 1999; 96: 11376-11381Crossref PubMed Scopus (226) Google Scholar). These differences, along with the absence of any data outside of mammals implicating cilia in the process of symmetry-breaking, have led many to argue that the underlying mechanisms might differ substantially between species, only converging onto a common genetic pathway during subsequent stages of L/R patterning (for further discussion, see 103Yost H.J Diverse initiation in a conserved left-right pathway?.Curr. Opin. Genet. Dev. 1999; 9: 422-426Crossref PubMed Scopus (54) Google Scholar). The key to reconciling these two conflicting views might lie in a more careful comparison of the actual timing of the early L/R patterning events described so far in mouse and chick. In the mouse, the development of nodal flow progresses through a series of well-defined stages, culminating in the establishment of a state of smooth, laminar leftward flow from the late neural plate to one-somite stage (64Okada Y Nonaka S Tanaka Y Saijoh Y Hamada H Hirokawa N Abnormal nodal flow precedes situs inversus in iv and inv mice.Mol. Cell. 1999; 4: 459-468Abstract Full Text Full Text PDF PubMed Scopus (351) Google Scholar). Shortly afterwards, the earliest molecular asymmetries (as marked by the leftward biased expression of the TGF-β superfamily members Nodal and lefty-1; Figure 2A) first begin to appear in small domains immediately adjacent to the node (15Collignon J Varlet I Robertson E.J Relationship between asymmetric nodal expression and the direction of embryonic turning.Nature. 1996; 381: 155-158Crossref PubMed Scopus (474) Google Scholar, 49Lowe L.A Supp D.M Sampath K Yokoyama T Wright C.V Potter S.S Overbeek P Kuehn M.R Conserved left-right asymmetry of nodal expression and alterations in murine situs inversus.Nature. 1996; 381: 158-161Crossref PubMed Scopus (405) Google Scholar, 53Meno C Saijoh Y Fujii H Ikeda M Yokoyama T Yokoyama M Toyoda Y Hamada H Left-right asymmetric expression of the TGFB-family member lefty in mouse embryos.Nature. 1996; 381: 151-155Crossref PubMed Scopus (367) Google Scholar, 54Meno C Ito Y Saijoh Y Matsuda Y Tashiro K Kuhara S Hamada H Two closely-related left-right asymmetrically expressed genes, lefty-1 and lefty-2 their distinct expression domains, chromosomal linkage and direct neuralizing activity in Xenopus embryos .Genes Cells. 1997; 2: 513-524Crossref PubMed Scopus (225) Google Scholar). 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Dev. 2000; 90: 115-118Crossref PubMed Scopus (33) Google Scholar) (stage 6; Figure 2B). However, in contrast to the mouse, where the presumptive initiating event (the onset of nodal flow) is followed immediately in time by the appearance of these small, asymmetric domains of Nodal and lefty-1 expression in the node region (without any intermediate stages), the initiating event in chick is clearly separated in time from the resulting asymmetries in Nodal and lefty-1 expression (as marked by the clear asymmetric expression patterns of several genes, including Shh and Fgf-8, prior to this stage). We would therefore like to postulate that these earlier asymmetric signaling cascades involving Shh and Fgf-8 have evolved to bridge a gap in time between the initiating event (the activity of nodal cilia?) and the transfer of L/R positional information from the node to the surrounding tissues. The postulated differences in the relative timing of nodal cilia function could, in turn, have been dictated by temporal and spatial constraints related to differences in the geometry of gastrulation in birds as compared to mammals. One important prediction of the model proposed above is that chick nodal cilia, if they do indeed exist and function in the breaking of symmetry, must be present and active prior to or coincident with the appearance of the earliest known molecular asymmetries in chick, that is, by late stage 3 or early stage 4 (43Levin M Johnson R.L Stern C.D Kuehn M Tabin C A molecular pathway determining left-right asymmetry in chick embryogenesis.Cell. 1995; 82: 803-814Abstract Full Text PDF PubMed Scopus (635) Google Scholar, 45Levin M Pagan S Roberts D.J Cooke J Kuehn M.R Tabin C.J Left/right patterning signals and the independent regulation of different aspects of situs in the chick embryo.Dev. Biol. 1997; 189: 57-67Crossref PubMed Scopus (180) Google Scholar). Similarly, if the activity of monocilia does represent a universal mechanism for specifying the L/R axis in vertebrates, we should expect to find cilia and other components of the ciliary machinery (including homologs of Lrd) present in the organizer region in other key vertebrate model systems such as Xenopus and zebrafish. Alternatively, it remains formally possible that a distinct mechanism, operating intracellularly and involving motor components shared with the ciliary machinery, serves an as yet undescribed role in the establishment of asymmetry. Still another scenario could be envisioned where a mechanism presumably unrelated to cilia sets up a program of asymmetric gene expression in the node. This last possibility is consistent with the observation that the perinodal region influences asymmetries in the chick node (65Pagán-Westphal S.M Tabin C.J The transfer of left-right positional information during chick embryogenesis.Cell. 1998; 93: 25-35Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar). These caveats notwithstanding, the cilia model, to its credit, has produced a number of testable hypotheses and remains the only model of L/R axis determination currently supported by empirical studies. Once small, stable domains of asymmetric gene expression are established in the node and perinodal area (Figure 2), these initial local asymmetries are converted into much broader domains of side-specific gene expression that subsequently coordinate the asymmetric development of the various organ primordia. At the molecular level, this is marked by the appearance of a second, broad domain of left-sided Nodal expression in the lateral plate mesoderm (LPM) (43Levin M Johnson R.L Stern C.D Kuehn M Tabin C A molecular pathway determining left-right asymmetry in chick embryogenesis.Cell. 1995; 82: 803-814Abstract Full Text PDF PubMed Scopus (635) Google Scholar, 15Collignon J Varlet I Robertson E.J Relationship between asymmetric nodal expression and the direction of embryonic turning.Nature. 1996; 381: 155-158Crossref PubMed Scopus (474) Google Scholar, 49Lowe L.A Supp D.M Sampath K Yokoyama T Wright C.V Potter S.S Overbeek P Kuehn M.R Conserved left-right asymmetry of nodal expression and alterations in murine situs inversus.Nature. 1996; 381: 158-161Crossref PubMed Scopus (405) Google Scholar). Significantly, left-specific expression of Nodal within the LPM has been observed in all vertebrates examined to date, and aberrant patterns of Nodal expression in the LPM are closely correlated with situs abnormalities in a variety of mutants and experimental situations (43Levin M Johnson R.L Stern C.D Kuehn M Tabin C A molecular pathway determining left-right asymmetry in chick embryogenesis.Cell. 1995; 82: 803-814Abstract Full Text PDF PubMed Scopus (635) Google Scholar, 45Levin M Pagan S Roberts D.J Cooke J Kuehn M.R Tabin C.J Left/right patterning signals and the independent regulation of different aspects of situs in the chick embryo.Dev. 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In the chick, Shh is both necessary and sufficient for inducing Nodal expression in the left LPM (43Levin M Johnson R.L Stern C.D Kuehn M Tabin C A molecular pathway determining left-right asymmetry in chick embryogenesis.Cell. 1995; 82: 803-814Abstract Full Text PDF PubMed Scopus (635) Google Scholar, 65Pagán-Westphal S.M Tabin C.J The transfer of left-right positional information during chick embryogenesis.Ce
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