The compulsion of chirality: toward an understanding of left-right asymmetry.

Abstract

Although it has long been clear that correct development of left–right (LR) asymmetry requires that tissues in the early embryo know whether they lie to the left or right of the midline, the molecular mechanisms that invariantly orient the LR axis have remained obscure. The recent demonstration that the iv (inverted viscerum) mutation in the mouse may be caused by a mutation in a gene encoding an axonemal dynein heavy chain has been much anticipated (Afzelius 1976; Brown et al. 1991; Levin and Nascone 1997) and sheds light on the earliest steps in the determination of LR asymmetry (Supp et al. 1997). However, many questions are also raised, such as what the roles of axonemal versus cytoplasmic dynein are, and how dynein action is transmitted across fields of cells, a prerequisite to the large-scale asymmetric gene expression known to be involved in determination of body asymmetry (Fujinaga 1996; Levin et al. 1997). In this review we discuss the nature of the information flow from molecular chirality to morphological and behavioral asymmetry as well as some possible molecular candidates for these processes. We also address the timing of initial LR decisions during embryogenesis, and evolutionary aspects of asymmetry. Most internal organs in the chest and abdomen of all vertebrates lie asymmetrically along the LR body axis despite external bilateral symmetry of the organism itself. In all normal individuals, the LR axis is invariantly oriented such that the apex of the heart points to the left, the aorta loops to the right and the inferior vena cava runs to the left of the spinal column. Similarly, the right lung is divided into three lobes whereas the left has only two. Beneath the diaphragm, the stomach and spleen are on the left and the intestine runs from right to left. Deviation from this normal pattern of asymmetry (situs solitus) can lead to complete mirror-image reversals of internal organ placement and anatomy (situs inversus) or randomization of organ situs (heterotaxy) as well as some loss of asymmetry (isomerism) (Burn 1991; WinerMuram 1995). Complete situs inversus does not appear to confer any adverse effects on the individual, yet, nonetheless, is estimated to occur in only 1/20,000 humans (although this is commonly thought to under-represent the actual number). Heterotaxia, in contrast, usually results in multiple abnormalities many of which, such as complex heart or vascular defects, are fatal without surgical intervention. Similarly, isomerisms such as Ivemark’s sequence (right isomerism, characterized by asplenia) as well as left isomerism (characterized by polysplenia) frequently compromise viability but, in less severe cases, may escape clinical detection (Burn 1991). A hallmark of most sporadic, familial, and experimentally-induced cases of laterality defects is that the organism does not lose its asymmetry; rather, individual organs (separately or together) can exhibit mirror-image asymmetry (Levin et al. 1995; Fujinaga 1996). This has led to the idea that asymmetric development or placement of an individual organ is distinct from the mechanism that orients the LR axis during development. In the absence of LR cues, therefore, the individual organs often become unbiased and develop with either normal or inverted asymmetry. The search for genes that control the overall pattern of asymmetry has provided some insight into early events leading to LR specification. The first demonstrations of asymmetric gene expression preceding organogenesis was made in chick embryos (Levin et al. 1995). Subsequent studies using mouse, Xenopus, and zebrafish embryos suggests that details of the left and right cascades of gene activation may not be conserved (Matzuk et al. 1995; Chiang et al. 1996; Collignon et al. 1996; Lowe et al. 1996); however, in all species examined, it appears that the left-sided gene cascade culminates in expression of nodal, which encodes a TGFb family member (Fig. 1, 2). An important aspect of the these studies is that misexpression of either leftor right-sided genes unbiases organ situs and leads to heterotaxia (Levin et al. 1997; Sampath et al. 1997). This, combined with the expression of the cascades prior to organogenesis, suggests that nodal and other downstream genes, such as lefty-1 and lefty-2 [also encoding TGFb family members (Meno et al. 1996)], provide LR cues to the developing organs. An important implication of this work is that mutations in these genes are likely to underlie both familial and sporadic cases of laterality defects in humans. This is likely to be the case for a familial X-linked situs abnormality that results from mutations in Zic3 (Gebbia et al. 1997), a gene encoding a zinc finger transcription factor. Interestingly, Zic3 shares structural similarity with the product of the Drosophila pair–rule gene odd paired (opa) and Corresponding author. E-MAIL mmercola@warren.med.harvard.edu; FAX (617) 432-1144.