Eukaryotic Cilia and Flagella, and Bardet-Biedl Syndrome (BBS)
Sixin Lu
sixin@caltech.edu
Bi 226
The paper to be presented:
Li, B.J., Gerdes, J.M., Haycraft, C.J., et al. (2004). Comparative Genomics Identifies a
Flagellar and Basal Body Proteome that Includes the BBS5 Human Disease Gene. Cell
117, 541-552.
http://www.cell.com/content/article/abstract?uid=PIIS0092867404004
507
A suggested review:
Dutcher, S.K. (2003). Elucidation of Basal Body and Centriole Functions in
Chlamydomonas reinhardtii. Traffic 4, 443-451.
http://www.blackwellsynergy.com/openurl?genre=article&sid=nlm:pubmed&issn=13989219&date=2003&volume=4&issue=7&spage=443
An optional review:
Snell, W.J., Pan, J., and Wang, Q. (2004). Cilia and Flagella Revealed: From Flagellar
Assembly in Chlamydomonas to Human Obesity Disorders. Cell 117, 693-697.
http://www.cell.com/content/article/abstract?uid=PIIS0092867404005
355
A totally optional review (only if you are curious about triallelic inheritance):
Katsanis, N. (2004). The Oligogenic Properties of Bardet-Biedl Syndrome. Hum. Mol.
Genet. 13, R65-R71.
http://hmg.oupjournals.org/cgi/content/abstract/13/suppl_1/R65
1. Cilia and Basal Bodies
Cilia are microtubule-based, whip-like cellular extensions that have essential
functions in cell motility or sensation. Cilia are important in development and
homeostasis (Snell et al., 2004).
CTRL + Click here to see a figure on cilium structure and
evolution (Avidor-Reiss et al., 2004).
Modified centrioles called basal bodies serve as templates from which ciliary
axonemes nucleate (Witman, 1990). A basal body is characterized by the nine radial
triplet microtubules arranged in a cartwheel pattern (See Fig. 2, Panel A of Dutcher,
2003).
The basal body docks proteins involved in intraflagellar transport (IFT) (Dutcher,
2003). The IFT machinery mediates the transport of flagellar components between the
cell body and flagellar compartments, and is essential for assembly and maintenance of
cilia and flagella in all eukaryotes (Snell et al., 2004).
2. Chlamydomonas reinhardtii
Chlamydomonas, a unicellular biflagellated alga, has basal bodies that
interconvert with centrioles (Alberts et al., 2002). During mitosis, the flagella are
resorbed, and basal bodies move to the interior of the cell to become part of the mitotic
spindle (Alberts et al., 2002). Recent studies found that the regulators of flagellar
assembly are homologs of mitotic proteins (Snell et al., 2004). Chlamydomonas is a
model organism in the study of flagella; its flagella and basal body proteins have high
homology to those of human (Li et al., 2004).
3. Bardet-Biedl Syndrome (BBS)
Human cilia diseases include two groups - polycystic kidney disease (PKD) and
primary cilia dyskinesia (PCD) (Snell et al., 2004). BBS is a rare, multi-system,
autosomal recessive disorder (Katsanis, 2001). It is characterized by a mixture between
disorders belonging to both groups (Snell et al., 2004). Although BBS is rare, interests to
identify BBS genes are due to the pleiotropic nature of BBS and commonness of
individual disease phenotypes, such as obesity and diabetes (Sheffield et al., 2001).
Clinical features of BBS are listed in the table below (Katsanis et al., 2001):
Li et al. compiled the flagellar and basal body (FABB) proteome consisting of
688 proteins by subtracting the nonflagellated genome of Arabidopsis from the shared
flagellated/ciliated genome of human and Chlamydomonas. The workers’ comparative
genomics methodology is based on the observation that nonflagellated organisms such as
Arabidopsis have lost most of the genes involved in flagellar assembly and maintenance.
When they narrowed down the FABB proteome to the proteins shared by C. elegans,
which has only nonmotile cilia, a proteome of 362 genes were obtained (Li et al., 2004).
The FABB proteome contained many known flagellar and basal body genes, as
well as some mammalian disease genes, such as BBS genes. Li et al. noticed that the
FABB proteome is enriched in domains associated with flagella, basal bodies and ciliated
neurons. In Chlamydomonas, 38% of the 103 genes taken from the FABB proteome were
upregulated after deflagellation (Li et al., 2004).
BBS5, the novel gene identified by Li et al., contributes approximately 2% to the
BBS mutation pool (Li et al., 2004). In C. elegans, a promoter motif called the X-box
was found in several genes need for functional cilia (Li et al., 2004). The FABB
proteome is enriched about 6-fold for C. elegans gene containing the X-box. Genes
downstream of X-box, including BBS5, are believed to be under regulatory control by
DAF-19 transcription factor. Li et al. confirmed that bbs5 transcription is indeed
regulated by DAF-19 in C. elegans. They also showed by RNAi that the BBS5 homolog
in Chlamydomonas plays a role in flagellar and basal body function and assembly (Li et
al., 2004).
BBS is associated with the failure of ciliogenesis. Eight loci have been mapped in
BBS, namely BBS1 through BBS8. The table below from a recent review (Beales, 2005)
summarizes the BBS genes:
4. Some Topics for Discussion
-What might be additional reasons why comparative genomics using different
organisms yielded slightly different flagellar and basal body proteomes? (see Table 1 of
Li et al.)
-Theories about the origin of eukaryotic flagellum include (Witman, 1990):
 the flagellum is derived from symbiotic bacteria with microtubule like
structures.
 the spindle evolved before the flagellum; and flagellum is formed due to
the aggregation of preexisting spindle microtubules.
 Chlamydomonas reinhardtii linkage group suggests that basal bodies
may be associated to an extranuclear genome.
Works Cited
Alberts, B., Johnson, A., Lewis, J., et al. (2002) The Cytoskeleton. In Molecular Biology
of the Cell. Garland Science, New York. 907-982.
Avidor-Reiss, T., Maer, A.M., Koundakjian, E., et al. (2004). Decoding Cilia Function:
Defining Specialized Genes Required for Compartmentalized Cilia Biogenesis. Cell 117,
527–539.
Beales, P.L. (2005). Lifting the lid on Pandora’s box: the Bardet-Biedl syndrome. Curr.
Opin. Genet. Dev. 15, 1-9. (Article in Press)
Katsanis, N., Lupski, J.R., and Beales, P.L. (2001). Exploring the Molecular Basis of
Bardet-Biedl Syndrome. Hum. Mol. Genet. 10, 2293-2299.
Li, B.J., Gerdes, J.M., Haycraft, C.J., et al. (2004). Comparative Genomics Identifies a
Flagellar and Basal Body Proteome that Includes the BBS5 Human Disease Gene. Cell
117, 541-552.
Sheffield, V.C., Nishimura, D., and Stone, E.M. (2001). The Molecular Genetics of
Bardet-Biedl Syndrome. Curr. Opin. Genet. Dev. 11, 317-321.
Snell, W.J., Pan, J., and Wang, Q. (2004). Cilia and Flagella Revealed: From Flagellar
Assembly in Chlamydomonas to Human Obesity Disorders. Cell 117, 693-697.
Witman, G.B. (1990) Introduction to Cilia and Flagella. In Ciliary and Flagellar
Membranes. R.A. Bloodgood, editor. Plenum Press, New York. 1-30.