Loss of function of the somatostatin receptor 3 (SSTR3), localized to cilia in the neocortex and hippocampus (Einstein et al., 2010 and Händel et al., 1999), leads to impaired object recognition in mice, whereas the loss of other SSTRs, not found on cilia, does not (Einstein et al., 2010). SSTR3 is evident in the brain only after mice are born (Stanić et al., 2009), implying that the phenotype depends on loss of signaling mediated by a ciliary Docetaxel manufacturer somatostatin receptor in mature neurons. Additionally, hippocampal long-term potentiation evoked with forskolin, a cAMP activator,

is significantly diminished in the Sstr3 mutant mouse ( Einstein et al., 2010). These findings finally link primary cilia with complex mammalian behavior Dolutegravir and brain plasticity. Primary cilia research is likely to continue its rapid growth. Also likely, however, is a new phase of

self-correction. Two main caveats need to be addressed. Several proteins that belong to the ciliary proteome additionally contribute to cellular processes outside the cilium, and more such extraciliary functions stand to be discovered. To state a few examples, several IFT proteins participate in the cytoplasmic vesicle pathway for exocytosis (Baldari and Rosenbaum, 2010); AHI1, associated with Joubert Syndrome, interacts with Rab8a, a small GTPase, also regulating vesicle trafficking (Hsiao et al., 2009); and certain BBS proteins are localized to additional microtubule motor complexes as well as the basal body (May-Simera et al., 2009 and Sen Gupta et al., 2009). Additionally, in mice,

Ahi1 is found in the adult kidney where it acts outside the cilium to upregulate β-catenin-mediated Wnt signaling. In adult Ahi1 null mice, reduced Wnt signaling, not ciliary defects, leads to cystic kidney disease ( Lancaster et al., 2009). Given that Ahi1 is expressed at several sites in mouse, including those the forebrain, decreased Wnt signaling could prove to cause a variety of abnormalities in patients with AHI1 mutations. These findings suggest that at least some abnormalities now termed ciliopathic in mouse models and human patients will be found to result from the disruption of cellular functions outside the cilium. Future studies are likely to amend substantially our current conclusions about the primary cilium and extend our understanding of disorders now termed ciliopathic. A second, related caveat is that in mice with deficiencies in an IFT protein or other ciliary protein, the brain phenotype may suggest a ciliary defect, yet ultrastructurally there may be little wrong with the cilium. Does this mean that a defective cilium is not central to the phenotype? Not necessarily. In the case of the cobblestone mutant mouse, in which cerebral cortical primary cilia appear normal, the signaling defect probably occurs at the cilium base where Gli3-FL is processed to Gli3R. A structural correlate may not be visible.