Functional Genomics of the Cilium, a Sensory Organelle

Abstract

Cilia and flagella play important roles in many physiological processes, including cell and fluid movement, sensory perception, and development. The biogenesis and maintenance of cilia depend on intraflagellar transport (IFT), a motility process that operates bidirectionally along the ciliary axoneme. Disruption in IFT and cilia function causes several human disorders, including polycystic kidneys, retinal dystrophy, neurosensory impairment, and Bardet-Biedl syndrome (BBS). To uncover new ciliary components, including IFT proteins, we compared C. elegans ciliated neuronal and nonciliated cells through serial analysis of gene expression (SAGE) and screened for genes potentially regulated by the ciliogenic transcription factor, DAF-19. Using these complementary approaches, we identified numerous candidate ciliary genes and confirmed the ciliated-cell-specific expression of 14 novel genes. One of these, C27H5.7a, encodes a ciliary protein that undergoes IFT. As with other IFT proteins, its ciliary localization and transport is disrupted by mutations in IFT and bbs genes. Furthermore, we demonstrate that the ciliary structural defect of C. elegans dyf-13(mn396) mutants is caused by a mutation in C27H5.7a. Together, our findings help define a ciliary transcriptome and suggest that DYF-13, an evolutionarily conserved protein, is a novel core IFT component required for cilia function.

IFT‐81 and IFT‐74 are required for intraflagellar transport in C. elegans

“…Many comprehensive studies using bioinformatics, genomics and proteomics have identified numerous putative ciliary proteins (Ostrowski et al 2002;AvidorReiss et al 2004;Li et al 2004;Blacque et al 2005;Efimenko et al 2005;Pazour et al 2005;Smith et al 2005;Stolc et al 2005). A recent work showed that a cGMP-dependent protein kinase (PKG) depending on IFT machinery participate in the flagellar-adhesion pathway in the alga Chlamydomonas, suggesting IFT has a direct role in cilium-based signaling (Scholey & Anderson 2006;Wang et al 2006;Yoder 2006).…”

Ciliary dysfunction impairs beta-cell insulin secretion and promotes development of type 2 diabetes in rodents

“…One of these proteins regulated by FoxO1, Syntaxin1A, interacts with the a1D subunit of the L-type voltage-gated Ca 2 þ channel 43 and is implicated in SNARE formation and insulin release 44 . An orthologue in C. elegans is regulated by daf-19, a transcription factor that is expressed in all ciliated sensory neurons 45,46 . We found Syntaxin1A (Stx1a) protein levels reduced by 25-30% in Bbs4-depleted islets and by 30-40% in Ofd1-depleted islets (Fig.…”

Joubert syndrome: genotyping a Northern European patient cohort

“…We included all genes from three studies by Andersen et al 13 (containing centrosomal located genes in human retinal cells), by Blacque et al, 14 and by Efimenko et al 15 (containing C. elegans genes that were selected because of an x-box upstream regulatory motif). [13][14][15] Given the fact that there is an excess of male patients in JBS, we also selected all X-linked ciliary genes (45 genes). We added 35 ciliary genes from chromosomal regions identified by homozygosity mapping (Human CNV370-Quadv3 Illumina bead array, Illumina, San Diego, CA, USA) in one consanguineous family.…”