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PMID:17331201

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Citation

Iijima, T, Miura, E, Matsuda, K, Kamekawa, Y, Watanabe, M and Yuzaki, M (2007) Characterization of a transneuronal cytokine family Cbln--regulation of secretion by heteromeric assembly. Eur. J. Neurosci. 25:1049-57

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.

Links

PubMed Online version:10.1111/j.1460-9568.2007.05361.x

Keywords

Amino Acid Sequence; Animals; Animals, Newborn; Biological Transport; Cells, Cultured; Cerebellum/cytology; Culture Media/chemistry; Endoplasmic Reticulum/metabolism; Endoplasmic Reticulum/ultrastructure; Gene Expression Regulation/physiology; Glycoproteins/secretion; Humans; Immunoprecipitation/methods; Mice; Mice, Knockout; Models, Biological; Nerve Tissue Proteins/deficiency; Nerve Tissue Proteins/physiology; Neurons/cytology; Neurons/metabolism; Neurons/ultrastructure; Protein Precursors/deficiency; Protein Structure, Tertiary/physiology; Sequence Alignment; Transfection/methods

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:CBLN2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q8BME9
PR:Q9JHG0
PR:Q9R171

F

Seeded From UniProt

complete

MOUSE:CBLN2

located_in

GO:0005615: extracellular space

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:CBLN4

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q8BGU2
PR:Q9JHG0
PR:Q9R171

F

Seeded From UniProt

complete

MOUSE:CBLN4

located_in

GO:0005615: extracellular space

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:CBLN3

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q8BGU2
PR:Q8BME9
PR:Q9R171

F

Seeded From UniProt

complete

MOUSE:CBLN3

located_in

GO:0045202: synapse

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0000121)
  • part_of:(EMAPA:17787)|part_of:(CL:0001031)
  • part_of:(EMAPA:17787)

Seeded From UniProt

complete

MOUSE:CBLN3

located_in

GO:0005615: extracellular space

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:88281

C

Seeded From UniProt

complete

MOUSE:CBLN1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q8BGU2
PR:Q8BME9
PR:Q9JHG0

F

Seeded From UniProt

complete

MOUSE:CBLN1

located_in

GO:0045202: synapse

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0001031)
  • part_of:(EMAPA:17787)|part_of:(CL:0000121)
  • part_of:(EMAPA:17787)

Seeded From UniProt

complete

MOUSE:CBLN1

acts_upstream_of_or_within

GO:0009306: protein secretion

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:0001031)
  • has_input:(MGI:MGI:1889286)

Seeded From UniProt

complete


See also

References

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