Calsyntenins are cadherin superfamily members that associate with scaffold proteins and amyloid precursor protein (APP) in neuronal cell membranes. Like APP, the extracellular domain of calsyntenin is released by proteolytic cleavage and the intracellular domain is endocytosed. Calsyntenins have been postulated to play a role in memory and learning in mammals, but no functional data have been reported. Ikeda et al. present genetic evidence that the extracellular domain of calsyntenin is required for learning in the nematode Caenorhabditis elegans. Animals carrying a null mutation in the single nematode calsyntenin gene CASY-1 failed to learn in three different behavioral conditioning assays in which the animals were taught to avoid a chemical (salt or benzaldehyde) or thermal cue by learning to associate that cue with starvation. CASY-1 mutants detected the cues in standard chemotaxis assays but could not learn to avoid them. Transient expression of CASY-1 in a single adult neuron (ASER) was sufficient to rescue the phenotype, which suggests that the learning deficiency did not result from a developmental defect. Furthermore, expression of just the extracellular domain of CASY-1 was sufficient to rescue the learning defect, leading the authors to suggest that the cleaved protein acts locally either on ASER itself or on a nearby neighbor. Given the shared trafficking pattern and close physical association between calsyntenins and APP, it was surprising to find that the intracellular domain of CASY-1 was not necessary for learning in the nematode. It will be interesting to see which domains are essential for mammalian calsyntenin function.
D. D. Ikeda, Y. Duan, M. Matsuki, H. Kunitomo, H. Hutter, E. M. Hedgecock, Y. Iino, CASY-1, an ortholog of calsyntenins/alcadeins, is essential for learning in Caenorhabditis elegans. Proc. Natl. Acad. Sci. U.S.A. 105, 5260-5265 (2008). [Abstract] [Full Text]