Trends in Genetics
Lateralization defects and ciliary dyskinesia: lessons from algae
Section snippets
Structure of flagella and cilia
The structure of cilia and flagella is similar in Chlamydomonas and humans 1, 10 (Fig. 2). Both organelles protrude from the cells and contain a highly organized scaffold of molecules called the axoneme. Usually, the axoneme is formed from ten pairs of microtubules, with nine peripheral pairs arranged around a central pair (i.e. a 9+2 formation; Fig. 2a). The peripheral pairs are each composed of a complete tubule (A) fused to a partial tubule (B). The central pair of microtubules are termed C1
Dynein arms
At least 28 Chlamydomonas mutants with different dynein arm anomalies have been characterized [10]. Mutations in the dynein IC78 of Chlamydomonas cause slow-swimming mutants with ultrastructural defects of the ODA [11]. Cloning of the orthologous human gene, DNAI1 (DN for dynein, A for axonemal and I for intermediate chain), showed that it is mutated in several, but not all, patients with PCD 12, 13. ODAs were absent from the five reported PCD patients carrying DNAI1 mutations, indicating that
Establishment of left–right asymmetry and the role of cilia
An important question that has recently received an answer concerns the relationship between ciliary function and body lateralization: why do half of PCD patients present with situs inversus?
The looping of the primitive heart tube to the right is the first evidence of lateralization in the embryo. It is thought that lateralization occurs in four steps: (1) initial breaking of bilateral symmetry; (2) establishment of asymmetric gene expression patterns within the embryonic organizer (the mouse
Left–right defects
Any type of disturbance of left–right polarity is termed collectively lateralization defect (LD) or heterotaxy. The incidence of LD is roughly 1 in 8000 births. A person with situs inversus and no other anomaly is symptom free. However, anomalies such as midline defects or ciliary dyskinesia that might be associated with situs inversus do cause symptoms. Furthermore, complications are frequent in incomplete left–right reversal (situs ambiguus). In situs ambiguus, the normal cardiac architecture
Conclusion
The molecular mechanisms controlling the normal growth and function of Chlamydomonas arms have obvious implications for the understanding of cilia and flagella in vertebrates. However, the kinetics of Chlamydomonas arms differ from vertebrate cilia and flagella. Moreover, these organelles in vertebrates have beating patterns that vary among tissues, and some cilia are immotile (e.g. monocilia of kidney epithelial cells). This versatility suggests that beside basic components, there are proteins
Acknowledgements
We thank Heidi Felix for electron microscopy; Bjorn Afzelius and the reviewers for their help in improving the manuscript; Mark Jorissen and Tom Willems for providing us with a picture of human respiratory epithelial cells in culture; and Julien Bouvagnet for his help in preparing the figures.
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