Loss of Bardet–Biedl syndrome proteins causes defects in peripheral sensory innervation and function

Abstract

Reception and interpretation of environmental stimuli is critical for the survival of all organisms. Here, we show that the ablation of BBS1 and BBS4, two genes mutated in Bardet-Biedl syndrome and that encode proteins that localize near the centrioles of sensory neurons, leads to alterations of s.c. sensory innervation and trafficking of the thermosensory channel TRPV1 and the mechanosensory channel STOML3, with concomitant defects in peripheral thermosensation and mechanosensation. The thermosensory phenotype is recapitulated in Caenorhabditis elegans, because BBS mutants manifest deficient thermosensory responses at both physiological and nociceptive temperatures and defective trafficking of OSM-9, a polymodal sensory channel protein and a functional homolog of TRPV1 or TRPV4. Our findings suggest a hitherto unrecognized, but essential, role for mammalian basal body proteins in the acquisition of mechano-and thermosensory stimuli and highlight potentially clinical features of ciliopathies in humans.basal bodies ͉ cilia ͉ thermosensation T he study of sensory organs in both vertebrates and invertebrates has revealed a role for cilia in chemosensation, mechanosensation, and photosensation. In Drosophila, chemosensation and mechanosensation rely specifically on neurons that are ciliated (1). Similarly, a role for cilia in chemosensation is well established in Caenorhabditis elegans, where mutants with compromised function or structure of cilia display defects in sensing odorants or differences in osmolarity (2-4). In mammals, odorant receptors localize to olfactory cilia (5), and the phototransduction apparatus of rod and cone cells in vertebrates localizes to the outer segment, a modified cilium (6). Finally, the kinocilium is essential for cochlear development and, thus, hearing because of its role in stereociliary bundle morphogenesis (7).We and others have shown that loss-of-function mutations in genes underlying the pleiotropic Bardet-Biedl phenotype (8) cause sensory deficits that include vision loss, anosmia, and defective hearing (5, 7, 9, 10). All BBS proteins characterized to date localize near or within basal bodies and in cilia in both mammalian cells (11-13) and in C. elegans sensory neurons (14-16).Here, we show that mammalian peripheral sensory neurons are ciliated and that mouse mutants with targeted loss-of-function mutations in either Bbs1 or Bbs4 exhibit thermosensory phenotypes characterized by significant increases in behavioral response latencies. These defects are unlikely to be caused by higher-order cortical or motor dysfunction but are accompanied by alterations in cutaneous sensory innervation and defective distribution of effector molecules in the sensory neuronal soma. These phenotypes are not unique to mammals, because nematode bbs mutants are also thermosensory-defective. Finally, humans with BBS also manifest some symptoms similar to the ones observed in mice, such as reduced temperature and vibration sensation. Our studies suggest a critical role of basal body and ciliary protein...

The AP-1 clathrin adaptor facilitates cilium formation and functions with RAB-8 in C. elegans ciliary membrane transport

“…2006; Qin et al, 2005;Tan et al, 2007). However, this might not be the case for all transmembrane proteins; for example, C. elegans ODR-10 targeting to AWB cilia was reported to require AP-1 complexes, but not IFT proteins (Dwyer et al, 2001).…”

Bardet–Biedl syndrome proteins are required for the localization of G protein-coupled receptors to primary cilia

“…Furthermore, ␤-tubulin III labeling did not reveal any alterations in microtubule structure in Bbs2 Ϫ/Ϫ or Bbs4 Ϫ/Ϫ neurons, which suggests that in some mammalian cells the function of the BBS proteins is to localize specific signaling proteins to cilia. A recent study showed altered distribution of the thermosensory channel TRPV1 and the mechanosensory channel STOML3 within the soma of peripheral neurons in BBS animals (33), suggesting that the BBS proteins may also contribute to trafficking of proteins within the cell body in some cell types.…”

Loss of Bardet–Biedl syndrome protein-8 (BBS8) perturbs olfactory function, protein localization, and axon targeting

“…This is consistent with considerable loss of cilia because these proteins are enriched in WT OSN cilia ( intense labeling in the dendrite and cell body in Bbs8 −/− compared with Bbs8 +/− mice; in addition, SLP3 expression was heterogeneous, with cells exhibiting variable staining intensity. SLP3 mislocalization has also been observed in dorsal root ganglion neurons of other BBS models (19). We next assessed the distribution of olfactory receptor (OR) protein in individual OSNs using an antibody against ORI7, expressed by ∼0.1% of OSNs.…”