Medicine positional information. Insight into upstream events that and Department of Genetics govern asymmetric gene expression has come from 2 Department of Internal Medicine study of mouse and human mutations affecting LR deand Department of Genetics velopment, which do not represent mutations in asym-3 Department of Pediatrics, Section of Cardiology metrically expressed genes. One of the best character-4 Department of Internal Medicine ized of these is the inversus viscerum (iv/iv) mouse Yale University School of Medicine (Hummel and Chapman, 1959). This mutation results in New Haven, Connecticut 06520 random development of LR asymmetry: 50% of liveborn iv/iv mice have normal orientation of the heart and viscera (situs solitus), the other 50% have a complete mirror Summary image reversal (situs inversus) (Layton, 1976). The expression of normally lateralized genes such as nodal, The vertebrate body plan has conserved handed leftlefty-2, and Pitx2 also becomes random: 25% of emright (LR) asymmetry that is manifested in the heart, bryos express nodal on the left, 25% on the right, 25% lungs, and gut. Leftward flow of extracellular fluid at bilaterally, and 25% do not express nodal in the lateral the node (nodal flow) is critical for normal LR axis plate mesoderm (Collignon et al., 1996; Lowe et al., determination in the mouse. Nodal flow is generated 1996). Iv is a point mutation in the left-right dynein (lrd) by motile node cell monocilia and requires the axogene, which encodes an outer arm axonemal (ciliary) nemal dynein, left-right dynein (lrd). In the absence of dynein (Supp et al., 1997). lrd, LR determination becomes random. The cation Kartagener syndrome is a human disease that results channel polycystin-2 is also required to establish LR in randomization of situs solitus and situs inversus (Afasymmetry. We show that lrd localizes to a centrally zelius, 1976), in addition to respiratory compromise and located subset of node monocilia, while polycystin-2 male infertility due to defective dynein function in the is found in all node monocilia. Asymmetric calcium tracheal cilia and in the sperm axoneme. At the molecusignaling appears at the left margin of the node coincilar level, Kartagener patients have defects in genes that dent with nodal flow. These observations suggest that encode several components of ciliary dynein (Olbrich et LR asymmetry is established by an entirely ciliary al., 2002; Bartoloni et al., 2002; Pennarun et al., 1999; mechanism: motile, lrd-containing monocilia generate Guichard et al., 2001). nodal flow, and nonmotile polycystin-2 containing cilia Targeted mutagenesis of two members of the heterosense nodal flow initiating an asymmetric calcium sigtrimeric kinesin family KIF3A (Marszalek et al., 1999; nal at the left border of the node. Takeda et al., 1999) and KIF3B (Nonaka et al., 1998) also result in ciliary defects, along with abnormal LR development, midgestation lethality, and multiple se-