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Molecular and Cellular Biology, December 2006, p. 9327-9337, Vol. 26, No. 24
0270-7306/06/$08.00+0     doi:10.1128/MCB.01161-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Cbln1 Is Essential for Interaction-Dependent Secretion of Cbln3

Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105,¹ Sanofi-Aventis, Bridgewater, New Jersey 08807²

Received 27 June 2006/ Returned for modification 17 August 2006/ Accepted 25 September 2006

Cbln1 and the orphan glutamate receptor GluR2 are pre- and postsynaptic components, respectively, of a novel transneuronal signaling pathway regulating synapse structure and function. We show here that Cbln1 is secreted from cerebellar granule cells in complex with a related protein, Cbln3. However, cbln1- and cbln3-null mice have different phenotypes and cbln1 cbln3 double-null mice have deficits identical to those of cbln1 knockout mice. The basis for these discordant phenotypes is that Cbln1 and Cbln3 reciprocally regulate each other's degradation and secretion such that cbln1-null mice lack both Cbln1 and Cbln3, whereas cbln3-null mice lack Cbln3 but have an approximately sixfold increase in Cbln1. Unlike Cbln1, Cbln3 cannot form homomeric complexes and is secreted only when bound to Cbln1. Structural modeling and mutation analysis reveal that, by constituting a steric clash that is masked upon binding Cbln1 in a "hide-and-run" mechanism of endoplasmic reticulum retention, a single arginine confers the unique properties of Cbln3.

Published ahead of print on 9 October 2006.

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