Abstract
Mutations and copy number variants of the CUB and Sushi Multiple Domains 2 (CSMD2) gene are associated with neuropsychiatric disease. CSMD2 encodes a single-pass transmembrane protein with a large extracellular domain comprising repeats of CUB and Sushi domains. High expression of CSMD2 in the developing and mature brain suggests possible roles in neuron development or function, but the cellular functions of CSMD2 are not known. In this study, we show that mouse Csmd2 is expressed in excitatory and inhibitory neurons in the forebrain. Csmd2 protein exhibits a somatodendritic localization in the neocortex and hippocampus, with smaller puncta localizing to the neuropil. Using immunohistochemical and biochemical methods, we demonstrate that Csmd2 localizes to dendritic spines and is enriched in the postsynaptic density. Accordingly, we show that the cytoplasmic tail domain of Csmd2 interacts with synaptic scaffolding proteins of the membrane-associated guanylate kinase (MAGUK) family. The association between Csmd2 and MAGUK member PSD-95 is dependent on a PDZ-binding domain on the Csmd2 tail, which is also required for synaptic targeting of Csmd2. Finally, we show that knockdown of Csmd2 expression in hippocampal neuron cultures results in reduced complexity of dendritic arbors and deficits in dendritic spine density. Knockdown of Csmd2 in immature developing neurons results in reduced filopodia density, whereas Csmd2 knockdown in mature neurons causes significant reductions in dendritic spine density and dendrite complexity. Together, these results point toward a function for Csmd2 in development and maintenance of dendrites and synapses, which may account for its association with certain psychiatric disorders.
Significance Statement Variants in the CUB and Sushi multiple domains (CSMD) genes have been associated with neuropsychiatric disorders that negatively affect cognitive and social performance. However, the mechanisms by which CSMD proteins contribute to proper brain function have yet to be understood. This study demonstrates that mouse Csmd2 is a synaptic protein that interacts with synaptic scaffold protein PSD-95. We also determine that Csmd2 is required for the development and maintenance of the dendritic arbor and dendritic spines of neurons. These results indicate that Csmd2 participates in the development and maintenance of synapses in the mammalian forebrain. Perturbation or loss of Csmd2 function could result in pathological conditions associated with neuropsychiatric disease.
Footnotes
Authors report no conflict of interest.
This work was supported by NIH/NCATS Colorado CTSA Grant Number UL1 TR002535 (S.J.F.), Children’s Hospital Colorado Program in Pediatric Stem Cell Biology (S.J.F.) and The Boettcher Foundation (S.J.F.).
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
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