The failure to establish midline body pattern and left-right asymmetry properly is an important cause of congenital malformations. These defects are associated with considerable morbidity and mortality secondary to complex congenital heart defects (CHD), immune dysfunction caused by abnormalities

The failure to establish midline body pattern and left-right asymmetry properly is an important cause of congenital malformations. These defects are associated with considerable morbidity and mortality secondary to complex congenital heart defects (CHD), immune dysfunction caused by abnormalities of spleen position or number, gut malrotation, and midline central nervous system (CNS) defects. ZIC3 was the first gene identified to have a causal role in defects of human laterality. Loss-of-function mutations in ZIC3 cause HTX1, which results in heterotaxy or situs ambiguus, the aberrant positioning of internal organs with respect to each other and the left-right (LR) axis. Carrier females who are heterozygous for a ZIC3 mutation are clinically unaffected although a subset has situs inversus, the mirror image reversal of internal anatomy (Casey et al., 1993; Gebbia et al., 1997). The molecular pathways required for correct LR axis specification and formation have been examined in different model organisms including Xenopus, chick, zebrafish and mouse (reviewed by Harvey, 1998; Burdine and Schier, 2000; Capdevila et al., 2000; Casey and Hackett, 2000). Pathways of asymmetric gene expression resulting in a cascade of lateralized signals that specify morphological asymmetry have been elucidated. This asymmetric gene expression is initiated at the node, or organizer, and occurs well before the first morphological sign of asymmetry, the rightward looping of the embryonic heart tube. These pathways appear to be conserved across species although the function of individual genes in the generation of LR asymmetry may be species specific. There are at least three major processes involved in establishment of the LR axis: (1) node-dependent symmetry breaking; (2) establishment of the embryonic midline (notochord and ventral floorplate); and (3) nodal-dependent signaling in the left lateral plate mesoderm (LPM). Failure in any of these processes will result in disturbances of laterality, including the complete reversal of left-right anatomy (situs inversus) or randomization of organ position (situs ambiguus). Generally, situs inversus is believed to arise as a result of an early event in which either the specification of asymmetry or orientation of the LR axis with respect to anteroposterior and dorsoventral axes is disrupted. Examples 2293 Development 129, 2293-2302 (2002) Printed in Great Britain © The Company of Biologists Limited 2002 DEV14525