Mutations in a Guanylate Cyclase GCY-35/GCY-36 Modify Bardet-Biedl Syndrome–Associated Phenotypes in Caenorhabditis elegans

The Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada.
PLoS Genetics (Impact Factor: 7.53). 10/2011; 7(10):e1002335. DOI: 10.1371/journal.pgen.1002335
Source: PubMed


Author Summary
Bardet-Biedl syndrome (BBS) is a genetically heterogeneous, multisystemic disorder. Defects to the cilium, an evolutionarily conserved organelle, cause ciliopathies, a growing class of diseases that includes BBS. BBS proteins are involved in the vesicular transport of proteins to the cilium and in the process of intraflagellar transport. Here we show that, in addition to sensory defects, Caenorhabditis elegans bbs mutants exhibit reduced body size and delayed developmental timing. The reduced body size phenotype is not fully recapitulated by IFT mutants, suggesting that BBS proteins may have additional functions beyond bridging IFT motors. We further identified that the loss of function mutations in the soluble guanylate cyclase complex, GCY-35/GCY-36, results in a suppression of these defects. Interestingly, GCY-35/GCY-36 influences the body size through a cGMP-dependent protein kinase EGL-4 in a group of body cavity neurons. BBS proteins, on the other hand, function through a non-overlapping set of ciliated sensory neurons to influence cGMP signalling in the body cavity neurons. In conclusion, this study reveals a non-cell autonomous role for sensory cilia in regulating cGMP signalling during development. We propose that aberrant cGMP signalling, essential for a number of cellular processes, may also contribute to some ciliopathy features in other systems.

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Available from: Mei Zhen, May 24, 2015
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    • "Signaling components that require BBS proteins for trafficking into (or out of) cilia include GPCR proteins, such as melanin-concentrating hormone receptor 1 (MCHR1), somatostatin receptor type 3 (SSTR3), dopamine receptor type 1 (D1) and rhodopsin (Nishimura et al., 2004; Berbari et al., 2008; Domire et al., 2011). Genetic studies implicate BBS proteins in cGMP signaling (Mok et al., 2011), but the molecular basis of their involvement remains undetermined. Another group of ciliary proteins linked to different ciliopathies, including nephronophthisis (NPHP), Meckel syndrome (MKS) and Joubert syndrome (JBTS), form part of a protein network present within the proximal-most region of the cilium (Reiter et al., 2012). "
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