Cbln1 is essential for interaction-dependent secretion of Cbln3

CbIn1 and the orphan glutamate receptor GluR delta 2 are pre- and postsynaptic components, respectively, of a novel transneuronal signaling pathway regulating synapse structure and function. We show here that CbIn1 is secreted from cerebellar granule cells in complex with a related protein, CbIn3. 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 CbIn1 and CbIn3 reciprocally regulate each other's degradation and secretion such that cbln1-null mice lack both CbInl and CbIn3, whereas cbln3-null mice lack CbIn3 but have an approximately sixfold increase in CbInl. Unlike CbInl, CbIn3 cannot form homomeric complexes and is secreted only when bound to CbInl. Structural modeling and mutation analysis reveal that, by constituting a steric clash that is masked upon binding CbInl in a "hide-and-run" mechanism of endoplasmic reticulum retention, a single arginine confers the unique properties of CbIn3.