Neuroanatomical Distribution of DEK Protein in Corticolimbic Circuits Associated with Learning and Memory in Adult Male and Female Mice

Abstract

DEK, a chromatin-remodeling gene expressed in most human tissues, is known for its role in cancer biology and autoimmune diseases. DEK depletion in vitro reduces cellular proliferation, induces DNA damage subsequently leading to apoptosis, and down-regulates canonical Wnt/β-catenin signaling, a molecular pathway essential for learning and memory. Despite a recognized role in cancer (non-neuronal) cells, DEK expression and function is not well characterized in the central nervous system. We conducted a gene ontology analysis (ToppGene), using a cancer database to identify genes associated with DEK deficiency, which pinpointed several genes associated with cognitive-related diseases (i.e., Alzheimer’s disease, presenile dementia). Based on this information, we examined DEK expression in corticolimbic structures associated with learning and memory in adult male and female mice using immunohistochemistry. DEK was expressed throughout the brain in both sexes, including the medial prefrontal cortex (prelimbic, infralimbic and dorsal peduncular). DEK was also abundant in all amygdalar subdivisions (basolateral, central and medial) and in the hippocampus including the CA1, CA2, CA3, dentate gyrus (DG), ventral subiculum and entorhinal cortex. Of note, compared to males, females had significantly higher DEK immunoreactivity in the CA1, indicating a sex difference in this region. DEK was co-expressed with neuronal and microglial markers in the CA1 and DG, whereas only a small percentage of DEK cells were in apposition to astrocytes in these areas. Given the reported inverse cellular and molecular profiles (e.g., cell survival, Wnt pathway) between cancer and Alzheimer’s disease, these findings suggest a potentially important role of DEK in cognition.

Sex differences in DEK expression in the anterior cingulate cortex and its association with dementia severity in schizophrenia

“…Notably, for all queried forebrain and hindbrain regions (e.g., various frontal cortical areas, striatum, amygdala, hippocampus, cerebellum), DEK mRNA expression was most prominent during the fetal developmental period compared to other developmental stages (adolescent, adult, elderly), suggesting a potential role in neural development. Consistent with these findings, we reported that DEK protein expression is ubiquitously expressed throughout the adult murine brain, with prominent expression in the medial prefrontal cortex, hippocampus proper, and amygdala in both sexes (Ghisays et al 2018). DEK is also robustly expressed in the developing mouse brain (unpublished findings).…”

“…Although DEK mRNA expression has been reported in the human brain (Kroes et al 2000), DEK protein localization with other cell types in human brain has yet to be examined. However, RNASeq analysis identified DEK in astrocytes and neurons, amongst other cell types, in rodent frontal cortex (Zhang et al 2014), and using immunohistochemistry, we report that DEK is co-expressed with neuronal, astroglial, and microglial markers in the hippocampus, albeit to varying degrees (Ghisays et al 2018).…”

“…We conducted a ToppGene analysis using human head and neck cancer cells to identify candidate diseases associated with DEK loss. Gene ontology analyses revealed a link between DEK deficiency and an upregulation in several candidate genes for various cognitive disorders (e.g., presenile dementia, subcortical vascular dementia, and age-related cognitive decline) (Ghisays et al 2018). The aforementioned cellular and molecular findings, coupled with the ToppGene analyses, suggest that DEK is a cognitive protective factor and that its deficiency may be linked with cognitive impairment.…”

Loss of DEK Expression Induces Alzheimer’s Disease Phenotypes in Differentiated SH-SY5Y Cells

“…Our group was the first to associate central nervous system-relevant diseases, such as AD, with decreased expression of the chromatin-binding protein DEK (Ghisays et al, 2018 ). Still, the cellular and molecular relevance of DEK expression in the brain is largely unexplored.…”

“…In 2018, a gene ontology analysis by our group found that AD, dementia, and other age-associated anomalies had transcriptomic signatures associated with DEK loss in human cells (Ghisays et al, 2018 ). Also, using human postmortem brain samples we found that lower DEK protein expression in the anterior cingulate cortex was correlated with increasing dementia severity in women, but not men (O’Donovan et al, 2018 ).…”