Cbln1 is essential for interaction-dependent secretion of Cbln3

Mol Cell Biol. 2006 Dec;26(24):9327-37. doi: 10.1128/MCB.01161-06. Epub 2006 Oct 9.


Cbln1 and the orphan glutamate receptor GluRdelta2 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cells, Cultured
  • Endoplasmic Reticulum / metabolism
  • Mice
  • Mice, Knockout
  • Molecular Sequence Data
  • Nerve Tissue Proteins / deficiency
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Nerve Tissue Proteins / physiology*
  • Phenotype
  • Protein Binding
  • Protein Precursors / deficiency
  • Protein Precursors / genetics
  • Protein Precursors / metabolism*
  • Protein Precursors / physiology*


  • Cbln1 protein, mouse
  • Cbln3 protein, mouse
  • Nerve Tissue Proteins
  • Protein Precursors