CASY-1, an ortholog of calsyntenins/alcadeins, is essential for learning in Caenorhabditis elegans

Daisuke D. Ikeda^*,, Yukan Duan, Masahiro Matsuki^*,,, Hirofumi Kunitomo^*, Harald Hutter^¶, Edward M. Hedgecock, and Yuichi Iino^*,,||

*Molecular Genetics Research Laboratory and Department of Biophysics and Biochemistry, Graduate School of Science, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan; Department of Biology, The Johns Hopkins University, Baltimore, MD 21218; and ^¶Department of Biological Sciences, Simon Fraser University, Burnaby, BC, Canada V5A 1S6

Received for publication December 18, 2007.

Abstract: Calsyntenins/alcadeins are type I transmembrane proteins with two extracellular cadherin domains highly expressed in mammalian brain. They form a tripartite complex with X11/X11L and APP (amyloid precursor protein) and are proteolytically processed in a similar fashion to APP. Although a genetic association of calsyntenin-2 with human memory performance has recently been reported, physiological roles and molecular functions of the protein in the nervous system are poorly understood. Here, we show that CASY-1, the Caenorhabditis elegans ortholog of calsyntenins/alcadeins, is essential for multiple types of learning. Through a genetic screen, we found that casy-1 mutants show defects in salt chemotaxis learning. casy-1 mutants also show defects in temperature learning, olfactory adaptation, and integration of two sensory signals. casy-1 is widely expressed in the nervous system. Expression of casy-1 in a single sensory neuron and at the postdevelopmental stage is sufficient for its function in salt chemotaxis learning. The fluorescent protein-tagged ectodomain of CASY-1 is released from neurons. Moreover, functional domain analyses revealed that both cytoplasmic and transmembrane domains of this protein are dispensable, whereas the ectodomain, which contains the LG/LNS-like domain, is critically required for learning. These results suggest that learning is modulated by the released ectodomain of CASY-1.

Key Words: ectodomain shedding • learning and memory

Present address: Innovative Biology Labs, R&D Eisai Co., Ltd., Tsukuba-shi, Ibaraki 300-2635, Japan.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0711894105/DCSupplemental.

^||To whom correspondence should be addressed. E-mail: iino{at}biochem.s.u-tokyo.ac.jp

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