Caspr2 interacts with type 1 inositol 1,4,5-trisphosphate receptor in the developing cerebellum and regulates Purkinje cell morphology.

The Journal of Biological Chemistry
Liam ArgentEsther B E Becker

Abstract

Contactin-associated protein-like 2 (Caspr2) is a neurexin-like protein that has been associated with numerous neurological conditions. However, the specific functional roles that Caspr2 plays in the central nervous system and their underlying mechanisms remain incompletely understood. Here, we report on a functional role for Caspr2 in the developing cerebellum. Using a combination of confocal microscopy, biochemical analyses, and behavioral testing, we show that loss of Caspr2 in the Cntnap2 -/- knockout mouse results in impaired Purkinje cell dendritic development, altered intracellular signaling, and motor coordination deficits. We also find that Caspr2 is highly enriched at synaptic specializations in the cerebellum. Using a proteomics approach, we identify type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) as a specific synaptic interaction partner of the Caspr2 extracellular domain in the molecular layer of the developing cerebellum. The interaction of the Caspr2 extracellular domain with IP3R1 inhibits IP3R1-mediated changes in cellular morphology. Together, our work defines a mechanism by which Caspr2 controls the development and function of the cerebellum and advances our understanding of how Caspr2 dysfunction might...Continue Reading

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Datasets Mentioned

BETA
PXD018972

Methods Mentioned

BETA
pull down
pulldown
immunoprecipitation
co-immunoprecipitation
confocal microscopy
transfection
PCR
size-exclusion chromatography
gel filtration

Software Mentioned

AxioVision
ImageJ
R binom package
Mascot Matrix Science
FV3000
Leica application suite
Graph Pad Prism
DataAnalysis
R
Mascot

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