Title : Characterization of a transneuronal cytokine family Cbln--regulation of secretion by heteromeric assembly
Abstract :
- Cbln1 , a member of the C1q and tumor necrosis factor superfamily, plays crucial roles as a cerebellar granule cell-derived transneuronal regulator of synapse integrity and plasticity in Purkinje cells
- Although other Cbln family members, Cbln2- Cbln4 , have distinct spatial and temporal patterns of expression throughout the CNS, their biochemical and biological properties have remained largely uncharacterized
- Here, we demonstrated that in mammalian heterologous cells, Cbln2 and Cbln4 were secreted as N-linked glycoproteins , like Cbln1
- In contrast, despite the presence of a functional signal sequence , Cbln3 was not secreted when expressed alone but was retained in the endoplasmic reticulum (ER) or cis-Golgi because of its N-terminal domain
- All members of the Cbln family formed not only homomeric but also heteromeric complexes with each other in vitro
- Accordingly, when Cbln1 and Cbln3 were co-expressed in heterologous cells, a proportion of the Cbln1 proteins was retained in the ER or cis-Golgi; conversely, some Cbln3 proteins were secreted together with Cbln1
- Similarly, in wild-type granule cells expressing Cbln1 and Cbln3 , Cbln3 proteins were partially secreted and reached postsynaptic sites on Purkinje cell dendrites, while Cbln3 was almost completely degraded in cbln1-null granule cells
- These results indicate that like Cbln1 , Cbln2 and Cbln4 may also serve as transneuronal regulators of synaptic functions in various brain regions
- Furthermore, heteromer formation between Cbln1 and Cbln3 in cerebellar granule cells may modulate each other's trafficking and signaling pathways; similarly, heteromerization of other Cbln family proteins may also have biological significance in other neurons