In the vertebrates, the unpaired organs of the chest and abdomen are positioned asymmetrically along the left-right (L-R) body axis. With respect to the midline, each organ resides non-randomly in an overall position which is designated situs solitus. For example, in humans, heart, stomach and spleen are consistently positioned to the left and the liver to the right of the midline. Aberrant development of the L-R axis can lead to randomization of individual organ position (situs ambiguus) or to mirror-image reversal of all lateralized structures (situs inversus).

The clear mechanism that accounts for L-R positioning is still not clear. However, a number of genes have been identified whose asymmetric expression in the embryo has suggested that they play a role in the left-ride side determination. Among these genes are activin receptor type IIA, sonic hedgehog (Shh) and cNR-1 which are expressed asymmetrically in the chicken embryos. In chick, the left-right side expression of the Shh is driven by the signals that originate adjacent to the node (Pagan-Westphal et al 1998). nodal is the mouse homolog of the chick cNR-1 and belongs to the TGF-beta superfamily of molecules. This gene is expressed in the lefty side of the body in the vertebrates including Xenopus, chick and mouse embryos. Snr-1 which encodes a zinc finger transcription factor is expressed in the right side of the chick embryo (Issac et al, 1997). Recently, Pitx2, the homolog of the human RIEG, a Bicoid-type homeobox gene has been identified which is also expressed in the left lateral plate mesoderm both in the chick and the mouse (Yoshioka et al, 1998). Pitx2 which is also called Otlx2, or Brx1 is expressed in the developing face, brain and limbs in the mouse embryos. Two additional genes, lefty-1 and lefty-2 are also expressed asymmetrically in the mouse embryos (Meno et al, 1996, 1997). Both genes belong to the TGF-beta superfamily. ebaf, the endometrial bleeding associated factor, is the human homolog of the mouse lefty-1 (Kothapalli et al, 1997). However, the human homolog of the mouse lefty-2 has not yet been identified. lefty-1 is predominantly expressed in the prospective floor plate (PFP) whereas the lefty-2 is expressed in the lateral plate mesoderm (LPM). In humans, the expression of a putative zinc finger transcription factor ZIC3 is associated with situs abnormalities. One frameshift, two missense and two nonsense mutations were identified in familial and sporadic situs ambiguus.

Some new studies are shedding light on the hierarchy of these genes. For example, the Shh seems to signal to the lateral plate mesoderm and induces the left sided expression of the nodal in the chick embryo. In mouse, two mutations, iv and inv, induce situs inversus. The gene which is affected by the iv mutation encodes a microtubule-based motor protein which is related to the axonemal dynein and is called left/right-dynein (lrd). Consistent with its role in left-right side development, lrd is expressed in the node of the embryo at embryonic day 7.5. The expression of the nodal, lefty-1 and lefty-2 seems to reside downstream from the iv and inv since the expression of these genes is affected in the iv and inv mutant mice. Meno et al in the August 7, 1998 issue of cell report that the expression of the lefty-1 is upstream from the expression of the lefty-2 and nodal (Meno et al, 1998). The gene knockout of the lefty-1 resulted in the bilateral expression of the nodal, lefty-2 and Pitx2 and was associated with thoracic left isomerism. The heterozygotes appeared normal. However, there was an increased number of deaths in the homozygotes starting at E10.5. About 60% of the embryos died in utero and only 5% (25/498) of homozygotes were alive at weaning. The most predominant defect in the homozygotes was monolobed lungs, a condition known as left pulmonary isomerism. In the normal mice, the bronchial tree develops asymmetrically. The right bronchus is larger in diameter and is shorter than the left bronchus and is located dorsal to the pulmonary artery. In the lefty-1 ^-/- homozygotes, however, the bronchial tree developed symmetrically. The development of the heart and the cardiac outflow tracts was also affected in the homozygotes. The right atrium developed abnormally and resembled the left atrium in its structure. Although the position of the heart was normal (levocardia), the position of the pulmonary and aorta and veins was frequently abnormal. Liver developed abnormally and lacked the caudate lobe. One of the mutant mice developed situs inversus. Based on the findings, the authors proposed a "midline barrier model" for the function of the lefty-1 and the regulation of lefty-1, lefty-2 and nodal. According to this model, the expression of these genes is regulated downstream from the iv and inv (figure). A hypothetical gene (X), which encodes a long-range signaling molecule, activates the lefty-2 and nodal and not lefty-1. lefty-1 or a protein induced by it antagonizes the action of the factor X to the right side of the body. When lefty-1 is absent, then factor X diffuses to the right side and activates the lefty-2 and nodal. There is some evidence that supports the existence of a midline barrier.

1. In Xenopus and zebrafish, midline structures play an essential role in establishing the L-R asymmetry.
2. In Xenopus, Xnr-1, similar to the lefty-2 and nodal in the mouse, is expresed in the left side. Removal of the midline structures results in the bilateral expression of the Xnr-1.
3. The nt (no turning) mutation in the mouse leads to the defects in the midline structures, laterality defects, lack of lefty in the PFP, and bilateral expression of nodal and lefty-2 in LPM.
4. In conjoined twins, laterality defects such as reversal of the heart situs is observed.
5. The expression of the nodal is aberrant in the conjoined twins in chick.

Based on these findings, Meno et al conclude that lefty-1 plays a role in the L-R asymmetry, and Lefty-1 protein is likely to serve as or induce a midline barrier and prevent the diffusion of a molecule that regulates the expression of the lefty-2 and nodal.

FIGURE LEGEND: The "midline barrier model". See text for explanation.

REFERENCES:

Meno C, et al.           [See Related Articles]

lefty-1 is required for left-right determination as a regulator of lefty-2 and nodal.
Cell. 1998 Aug 7; 94(3): 287-297.
PMID: 9708731; UI: 98372436.

Oulad-Abdelghani M, et al.           [See Related Articles]

Stra3/lefty, a retinoic acid-inducible novel member of the transforming growth factor-beta superfamily.
Int J Dev Biol. 1998 Jan; 42(1): 23-32.
PMID: 9496783; UI: 98156497.

Melloy PG, et al.           [See Related Articles]

No turning, a mouse mutation causing left-right and axial patterning defects.
Dev Biol. 1998 Jan 1; 193(1): 77-89.
PMID: 9466889; UI: 98133992.

Supp DM, et al.           [See Related Articles]

Mutation of an axonemal dynein affects left-right asymmetry in inversus viscerum mice.
Nature. 1997 Oct 30; 389(6654): 963-966.
PMID: 9353118; UI: 98013167.

Meno C, et al.           [See Related Articles]

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 Aug; 2(8): 513-524.
PMID: 9348041; UI: 98006264.

Heymer J, et al.           [See Related Articles]

The expression pattern of nodal and lefty in the mouse mutant Ft suggests a function in the establishment of handedness.
Mech Dev. 1997 Aug; 66(1-2): 5-11.
PMID: 9376323; UI: 98025477.

Meno C, et al.           [See Related Articles]

Left-right asymmetric expression of the TGF beta-family member lefty in mouse embryos.
Nature. 1996 May 9; 381(6578): 151-155.
PMID: 8610011; UI: 96202359.

Beddington R.           [See Related Articles]

Left, right, left... turn.
Nature. 1996 May 9; 381(6578): 116-117. No abstract available.
PMID: 8610005; UI: 96202353.

Goldblatt D.           [See Related Articles]

Writing for lefty.
Semin Neurol. 1991 Dec; 11(4): 419-423. No abstract available.
PMID: 1811297; UI: 92245249.

Horgan J.           [See Related Articles]

So long, lefty.
Sci Am. 1988 Aug; 259(2): 26-27. No abstract available.
PMID: 3217784; UI: 89114364.

Baum ME.           [See Related Articles]

"Say good-bye to Lefty".
Nursing. 1979 Dec; 9(12): 47-48. No abstract available.
PMID: 390428; UI: 80078553.

Supp DM, et al.           [See Related Articles]

Mutation of an axonemal dynein affects left-right asymmetry in inversus viscerum mice.
Nature. 1997 Oct 30; 389(6654): 963-966.
PMID: 9353118; UI: 98013167.

Supp DM, et al.           [See Related Articles]

Handed asymmetry in the mouse: understanding how things go right (or left) by studying how they go wrong.
Semin Cell Dev Biol. 1998 Feb; 9(1): 77-87. Review.
PMID: 9572117; UI: 98233644.

Lowe LA, et al.           [See Related Articles]

Conserved left-right asymmetry of nodal expression and alterations in murine situs inversus.
Nature. 1996 May 9; 381(6578): 158-161.
PMID: 8610013; UI: 96202361.

Brueckner M, et al.           [See Related Articles]

Establishment of left-right asymmetry in vertebrates: genetically distinct steps are involved.
Ciba Found Symp. 1991; 162: 202-212. Review.
PMID: 1802643; UI: 92201027.

Levin M, et al.           [See Related Articles]

Two molecular models of initial left-right asymmetry generation.
Med Hypotheses. 1997 Nov; 49(5): 429-435. Review.
PMID: 9421811; UI: 98083589.

Yokoyama T, et al.           [See Related Articles]

Reversal of left-right asymmetry: a situs inversus mutation.
Science. 1993 Apr 30; 260(5108): 679-682.
PMID: 8480178; UI: 93242394.

Brown NA, et al.           [See Related Articles]

The development of asymmetry: the sidedness of drug-induced limb abnormalities is reversed in situs inversus mice.
Development. 1989 Nov; 107(3): 637-642.
PMID: 2612382; UI: 90126393.

McGrath J, et al.           [See Related Articles]

Duplication/deficiency mapping of situs inversus viscerum (iv), a gene that determines left-right asymmetry in the mouse.
Genomics. 1992 Nov; 14(3): 643-648.
PMID: 1427890; UI: 93052394.

Lander A, et al.           [See Related Articles]

Left-right development: mammalian phenotypes and conceptual models.
Semin Cell Dev Biol. 1998 Feb; 9(1): 35-41. Review.
PMID: 9572112; UI: 98233639.

Meno C, et al.           [See Related Articles]

Left-right asymmetric expression of the TGF beta-family member lefty in mouse embryos.
Nature. 1996 May 9; 381(6578): 151-155.
PMID: 8610011; UI: 96202359.

Li M, et al.           [See Related Articles]

Drosophila cytoplasmic dynein, a microtubule motor that is asymmetrically localized in the oocyte.
J Cell Biol. 1994 Sep; 126(6): 1475-1494.
PMID: 8089180; UI: 94375524.

Brown NA, et al.           [See Related Articles]

The development of handedness in left/right asymmetry.
Development. 1990 May; 109(1): 1-9. Review.
PMID: 2209459; UI: 91005858.

Layton WM Jr.           [See Related Articles]

Random determination of a developmental process: reversal of normal visceral asymmetry in the mouse.
J Hered. 1976 Nov; 67(6): 336-338.
PMID: 1021593; UI: 77141727.

Melloy PG, et al.           [See Related Articles]

No turning, a mouse mutation causing left-right and axial patterning defects.
Dev Biol. 1998 Jan 1; 193(1): 77-89.
PMID: 9466889; UI: 98133992.

Brown NA, et al.           [See Related Articles]

Development of the left-right axis.
Ciba Found Symp. 1992; 165: 144-154. Review.
PMID: 1516466; UI: 92387032.

McCarthy A, et al.           [See Related Articles]

Specification of left-right asymmetry in mammals: embryo culture studies of stage of determination and relationships with morphogenesis and growth.
Reprod Toxicol. 1998 Mar; 12(2): 177-184.
PMID: 9535512; UI: 98195190.

Meno C, et al.           [See Related Articles]

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 Aug; 2(8): 513-524.
PMID: 9348041; UI: 98006264.

Brown NA, et al.           [See Related Articles]

The development of handed asymmetry in aggregation chimeras of situs inversus mutant and wild-type mouse embryo.
Development. 1990 Nov; 110(3): 949-954.
PMID: 2088730; UI: 91209250.

Holzbaur EL, et al.           [See Related Articles]

Homology of a 150K cytoplasmic dynein-associated polypeptide with the Drosophila gene Glued.
Nature. 1991 Jun 13; 351(6327): 579-583.
PMID: 1828535; UI: 91260877.

Singh G, et al.           [See Related Articles]

legless insertional mutation: morphological, molecular, and genetic characterization.
Genes Dev. 1991 Dec; 5(12A): 2245-2255.
PMID: 1748282; UI: 92084098.

Kothapalli R, et al.           [See Related Articles]

Detection of ebaf, a novel human gene of the transforming growth factor beta superfamily association of gene expression with endometrial bleeding.
J Clin Invest. 1997 May 15; 99(10): 2342-2350. Full manuscript
PMID: 9153275; UI: 97298127.