Bardet-Biedl syndrome (BBS) is an autosomal recessive, genetically heterogeneous, pleiotropic disorder. Cardinal features include photoreceptor degeneration, obesity, digit anomalies, kidney anomalies, cognitive impairment and hypogonadism. Most BBS genes encode ciliary proteins related to the intraflagellar transport (IFT) system. Consistently, C. elegans bbs mutants have defects in ciliary morphology and function (Blacque et al., 2004, Tan et al., 2007). We took a systematic approach to examine the common phenotypes shared by all bbs mutants. In addition to their known structural and functional defects in sensory cilia, all bbs mutants share a statistically significant loss of 15-20% in mean body length and a moderate decrease in body width. Olfactory neurosensory defects in C. elegans have been associated with decreased body length (Fujiwara et al., 2002) and increased fat accumulation (Mak et al., 2006). The transforming growth factor beta (TGF-beta) superfamily of proteins encompasses those in a pathway that also controls body size (Patterson and Padgett, 2000). Our genetic analyses between bbs and TGF-beta mutants (
dbl-1 and
lon-2) however suggested that their body size defects are additive. To understand how BBS proteins modulate body size, we identified a genetic suppressor that restored the reduced body size of bbs mutants to normal length and it encodes the guanylate cyclase GCY-35. Interestingly, while capable of suppressing bbs body size defects, mutations in
gcy-35 do not rescue the structure and function of the amphid sensory neurons in bbs mutants. Instead, GCY-35 is present and required in a subset of the O2 sensory neurons (Cheung et al., 2004, Gray et al., 2004, Chang et al., 2006) to regulate body size, and its localisation is unaffected in
bbs-7 mutants. BBS proteins, on the other hand, are required in the non-overlapping sensory neurons to regulate body size. The body size defects of bbs mutants are thus likely due to a defect in cGMP levels. Consistently, the body size change induced by both loss and gain of function mutants in cGMP-dependent kinase EGL-4 (Fujiwara et al., 2002) appear genetically epistatic to the body defects in bbs mutants, suggesting it as the downstream effector of the BBS complex in sensory cilia. The non-cell autonomous control of body size through guanylate cyclases in a small subset of ciliated neurons identifies an interesting direction for the further dissection of body size defects in C. elegans and later study of our human BBS cohorts. Acknowledgements. Cori Bargmann, and Mario De Bono for reagents. CIHR, VSRP, and Mira Godard Foundation for funding this project.