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PNAS 105 (13): 5260-5265

Copyright © 2008 by the National Academy of Sciences.


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

Daisuke D. Ikeda*,{dagger}, Yukan Duan{ddagger}, Masahiro Matsuki*,{dagger},§, Hirofumi Kunitomo*, Harald Hutter, Edward M. Hedgecock{ddagger}, and Yuichi Iino*,{dagger},||

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

Edited by Cornelia I. Bargmann, The Rockefeller University, New York, NY, and approved February 4, 2008

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

Author contributions: D.D.I., H.K., E.M.H., and Y.I. designed research; D.D.I., Y.D., M.M., and Y.I. performed research; D.D.I., Y.D., and H.H. contributed new reagents/analytic tools; D.D.I., H.K., and Y.I. analyzed data; and D.D.I., H.K., H.H., and Y.I. wrote the paper.

§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

||To whom correspondence should be addressed. E-mail: iino{at}

© 2008 by The National Academy of Sciences of the USA

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