Affiliation:
1. Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105
2. Sanofi-Aventis, Bridgewater, New Jersey 08807
Abstract
ABSTRACT
Cbln1 and the orphan glutamate receptor GluRδ2 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.
Publisher
American Society for Microbiology
Subject
Cell Biology,Molecular Biology
Cited by
48 articles.
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