Neuropsychological Deficits in Mice Depleted of the Schizophrenia Susceptibility Gene CSMD1

Steen, Vidar M.; Nepal, Chirag; Ersland, Kari Merete; Holdhus, Rita; Nævdal, Marianne; Ratvik, Siri M.; Skrede, Sverre; Håvik, Bjarte

doi:10.1371/journal.pone.0079501

Cited by 75 publications

(79 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…CSMD1 is highly expressed in human brain and testes [24], which is similar to the observed expression in central nervous system and epithelial tissues in rat [25]. In mice, expression was detected mainly in the central nervous system but also in visceral fat and ovaries [26]. The gene encoding human CSMD1 encompasses 70 exons located on chromosome 8p23.1 [27].…”

Section: Mac: Cell Lysissupporting

confidence: 67%

“…CSMD1 is highly expressed in brain, and genetic studies have linked mutations and polymorphisms in CSMD1 with schizophrenia , cognitive function and multiple sclerosis . Interestingly, knockout mice lacking CSMD1 display neuropsychological deficits . It is not yet clear whether this function of CMSD1 is directly related to its ability to regulate complement.…”

Section: Cub and Sushi Multiple Domains 1: Complement Inhibitor Tumomentioning

confidence: 99%

See 1 more Smart Citation

The role of complement inhibitors beyond controlling inflammation

Blom

2017

J Intern Med

View full text Add to dashboard Cite

Abstract. Blom AM (Lund University, Malm€ o, Sweden). The role of complement inhibitors beyond controlling inflammation (Review). J Intern Med 2017; 282: 116-128.The complement system is an arm of innate immunity that aids in the removal of pathogens and dying cells. Due to its harmful, pro-inflammatory potential, complement is controlled by several soluble and membrane-bound inhibitors. This family of complement regulators has been recently extended by the discovery of several new members, and it is becoming apparent that these proteins harbour additional functions. In this review, the current state of knowledge of the physiological functions of four complement regulators will be described: cartilage oligomeric matrix protein (COMP), CUB and sushi multiple domains 1 (CSMD1), sushi domain-containing protein 4 (SUSD4) and CD59. Complement activation is involved in both the development of and defence against cancer. COMP expression is pro-oncogenic, whereas CSMD1 and SUSD4 act as tumour suppressors. These effects may be related in part to the complex influence of complement on cancer but also depend on unrelated functions such as the protection of cells from endoplasmic reticulum stress conveyed by intracellular COMP. CD59 is the main inhibitor of the membrane attack complex, and its deficiency leads to complement attack on erythrocytes and severe haemolytic anaemia, which is now amenable to treatment with an inhibitor of C5 cleavage. Unexpectedly, the intracellular pool of CD59 is crucial for insulin secretion from pancreatic b-cells. This finding is one of several relating to the intracellular functions of complement proteins, which until recently were only considered to be present in the extracellular space. Understanding the alternative functions of complement inhibitors may unravel unexpected links between complement and other physiological systems, but is also important for better design of therapeutic complement inhibition.

show abstract

Section: Mac: Cell Lysissupporting

confidence: 67%

Section: Cub and Sushi Multiple Domains 1: Complement Inhibitor Tumomentioning

confidence: 99%

The role of complement inhibitors beyond controlling inflammation

Blom

2017

J Intern Med

View full text Add to dashboard Cite

show abstract

“…In future studies, it would be interesting to investigate mammary gland morphogenesis using an available CSMD1 knockout mouse model (43). Whole mounts of mouse fat pads would be prepared at 1, 14, 21, 28, 35 days after parturition and the ductal network and terminal buds compared between Csmd1 (-/-) and wild type (+/+) litter mates.…”

Section: Discussionmentioning

confidence: 99%

Loss of CSMD1 expression disrupts mammary duct formation while enhancing proliferation, migration and invasion

et al. 2017

View full text Add to dashboard Cite

Abstract. The CUB and sushi multiple domains 1 (CSMD1) gene maps to chromosome 8p23, a region deleted in many cancers. Loss of CSMD1 expression is associated with poor prognosis in breast cancer suggesting that it acts as a tumour suppressor in this cancer. However, the function of CSMD1 is largely unknown. Herein, we investigated CSMD1 functions in cell line models. CSMD1 expression was suppressed in MCF10A and LNCaP cells using short hairpin RNA. Functional assays were performed focusing on the 'normal' MCF10A cell line. Suppression of CSMD1 significantly increased the proliferation, cell migration and invasiveness of MCF10A cells compared to shcontrols. shCSMD1 cells also showed significantly reduced adhesion to Matrigel and fibronectin. In a three-dimensional Matrigel model of MCF10A cells, reduced CSMD1 expression resulted in the development of larger and more poorly differentiated breast acini-like structures that displayed impaired lumen formation. Loss of CSMD1 expression disrupts a model of mammary duct formation while enhancing proliferation, migration and invasion. Our data suggest that CSMD1 is involved in the suppression of a transformed phenotype. IntroductionCUB and sushi multiple domains-1 (CSMD1) is a very large gene which contains 71 exons that span over 2 Mb of genomic DNA on chromosome 8p23 (1). Multiple splice variants exist for CSMD1 and these encode proteins of varying length. The largest transcript is 14.3 kb long and this encodes a 3,565 amino acid protein (1). The full-length protein is a membrane protein with an extracellular region containing 14 CUB and 28 sushi domains, a single transmembrane domain and a short cytoplasmic domain that contains a putative tyrosine phosphorylation site. CSMD1 belongs to the CSMD gene family whose members also include the structurally similar proteins CSMD2 and CSMD3 (1-3). The function of CSMD1 is largely unknown. Although CSMD1 has been shown to inhibit C3 deposition onto the surface of cells leading to the inhibition of the classical complement pathway (4,5). The structure of CSMD1 predicts that CSMD1 is a receptor for unknown ligand(s) and is involved in signal transduction (1).CSMD1 is believed to act as a tumour suppressor based on a number of observations. CSMD1 is located on chromosome 8p23, a region that is frequently deleted in different types of cancer (1,6-10). In addition, reduced CSMD1 mRNA and protein expression has been observed in different cancers (11-17). An array comparative genomic hybridization study revealed a high rate of loss of 8p23.2 containing the CSMD1 gene in advanced prostrate cancer samples. A further small real-time PCR study identified a decrease in CSMD1 mRNA levels in higher stage prostrate cancer samples (11). Similarly reduced CSMD1 expression at the mRNA level has been identified in colorectal cancer associated with reduced patient survival (12). Furthermore, somatic mutations were detected in CSMD1 in 11% (6/54) of colorectal cancer patients along side DNA methylation and allele loss, predominantly in early onset ...

show abstract

“…The genes ZFPM2 , MTMR7 , and JAG1 have been implicated in CNS-related functions (Mochizuki and Majerus 2003; Ables et al 2011; Nielsen et al 2013). The CSMD1 gene has been implicated in schizophrenia (Håvik et al 2011; Ripke et al 2014) and in neuropsychological deficits in a mouse model (Steen et al 2013). Further, the GWAS data were mined for polymorphisms implicated in previous reports on candidate genes and recent genome-wide studies of WM FA (Lopez et al 2012; Jahanshad et al 2013b; Sprooten et al 2014) and the findings from two large GWASs of brain volumetric measures (Stein et al 2012; Hibar et al 2015) (Supplementary Table 2).…”

Section: Resultsmentioning

confidence: 99%

“…The Fisher’s combined P value method identified the highest significance (Fisher P value = 1 × 10 −07 ) for a SNP 14 kb downstream of the CSMD1 gene, which has been implicated in schizophrenia (Håvik et al 2011; Ripke et al 2014). CSMD1 is also relevant at the functional level, since it has been implicated in neuropsychological deficits in the mouse (Steen et al 2013). In addition, an intronic SNP in ZFPM2 was identified in the analysis of shared associations.…”

Section: Discussionmentioning

confidence: 99%

Genetics of structural connectivity and information processing in the brain

et al. 2016

Self Cite

View full text Add to dashboard Cite

Understanding the genetic factors underlying brain structural connectivity is a major challenge in imaging genetics. Here, we present results from genome-wide association studies (GWASs) of whole-brain white matter (WM) fractional anisotropy (FA), an index of microstructural coherence measured using diffusion tensor imaging. Data from independent GWASs of 355 Swedish and 250 Norwegian healthy adults were integrated by meta-analysis to enhance power. Complementary GWASs on behavioral data reflecting processing speed, which is related to microstructural properties of WM pathways, were performed and integrated with WM FA results via multimodal analysis to identify shared genetic associations. One locus on chromosome 17 (rs145994492) showed genome-wide significant association with WM FA (meta P value = 1.87 × 10−08). Suggestive associations (Meta P value <1 × 10−06) were observed for 12 loci, including one containing ZFPM2 (lowest meta P value = 7.44 × 10−08). This locus was also implicated in multimodal analysis of WM FA and processing speed (lowest Fisher P value = 8.56 × 10−07). ZFPM2 is relevant in specification of corticothalamic neurons during brain development. Analysis of SNPs associated with processing speed revealed association with a locus that included SSPO (lowest meta P value = 4.37 × 10−08), which has been linked to commissural axon growth. An intergenic SNP (rs183854424) 14 kb downstream of CSMD1, which is implicated in schizophrenia, showed suggestive evidence of association in the WM FA meta-analysis (meta P value = 1.43 × 10−07) and the multimodal analysis (Fisher P value = 1 × 10−07). These findings provide novel data on the genetics of WM pathways and processing speed, and highlight a role of ZFPM2 and CSMD1 in information processing in the brain.Electronic supplementary materialThe online version of this article (doi:10.1007/s00429-016-1194-0) contains supplementary material, which is available to authorized users.

show abstract

Neuropsychological Deficits in Mice Depleted of the Schizophrenia Susceptibility Gene CSMD1

Cited by 75 publications

References 44 publications

The role of complement inhibitors beyond controlling inflammation

The role of complement inhibitors beyond controlling inflammation

Loss of CSMD1 expression disrupts mammary duct formation while enhancing proliferation, migration and invasion

Genetics of structural connectivity and information processing in the brain

Contact Info

Product

Resources

About