Abstract
BackgroundDiscoidin domain receptor tyrosine kinase 1 (DDR1) is present in multiple types of epithelial cells and is highly expressed in the nervous system. Previous studies have revealed that DDR1 is involved in schizophrenia (SCZ). Although the expression of DDR1 in oligodendrocytes has been described, its role in brain myelination is not well understood. In this study, we aimed to explore the coexpression network of DDR1 in the human brain and to compare the list of DDR1 coexpressing genes with the list of genes containing single nucleotide polymorphisms (SNPs) that are associated with SCZ.Materials and MethodsWe used a weighted gene coexpression network analysis (WGCNA) of a dataset from four brain areas (the dorsolateral prefrontal cortex, primary motor cortex, hippocampus, and striatum) and from four different intervals (I) of life (I‐1 = 10–38 weeks postconception, I‐2 ≥0 to < 6 years, I‐3 ≥ 6 to < 40 years, and I‐4 ≥ 40 years of age). We compared the list of genes that are associated with SCZ in the GWAS Catalog with the list of genes coexpressing with DDR1 in each interval.ResultsOur study revealed that DDR1 was coexpressed with oligodendrocyte‐related genes mainly in I‐2 (adjP = 5.66e‐24) and I‐3 (adjP = 2.8e‐114), which coincided with the coexpression of DDR1 with myelination‐related genes (adjP = 9.04e‐03 and 2.51e‐08, respectively). DDR1 was also coexpressed with astrocyte‐related genes in I‐1 (adjP = 1.11e‐71), I‐2 (adjP = 2.12e‐20) and I‐4 (adjP = 9.93e‐52) and with type 2 microglia‐related genes in I‐1 (adjP = 2.84e‐08), I‐2 (adjP = 5.68e‐16) and I‐4 (adjP = 3.66e‐10). Moreover, we observed significant enrichment of SCZ susceptibility genes within the coexpression modules containing DDR1 in I‐1 and I‐4 (P = 1e‐04 and 0.0037, respectively), during which the DDR1 module showed the highest association with the astrocytes.ConclusionsOur study confirmed that DDR1 is coexpressed with oligodendrocyte‐ and myelin‐related genes in the human brain but suggests that DDR1 may contribute mainly to SCZ risk through its role in other glial cell types, such as astrocytes.
Highlights
Discoidin domain receptor tyrosine kinase 1 (DDR1) is a membraneanchored protein activated by fibrillar collagens (Leitinger, 2014)
Our study confirmed that DDR1 is coexpressed with oligodendrocyteand myelin-related genes in the human brain but suggests that DDR1 may contribute mainly to SCZ risk through its role in other glial cell types, such as astrocytes
With the primary hypotheses that DDR1 is upregulated during oligodendrocyte myelination and that DDR1 is itself or through its interaction with other genes associated with SCZ, we aimed to identify the genes coexpressed with DDR1 in human brain tissue in different neurodevelopmental periods and to test whether DDR1 is coexpressed with SCZ-associated genes
Summary
Discoidin domain receptor tyrosine kinase 1 (DDR1) is a membraneanchored protein activated by fibrillar collagens (Leitinger, 2014). Recent single-cell RNA-seq studies in rodent models reported that ddr expression peaks in the period in which newly formed oligodendrocytes differentiate into myelinating oligodendrocytes (Vilella et al, 2019). Data from these studies demonstrated that genes encoding the membrane receptors Ephrinb (Efnb3), plexinb (Plxnb3), ERBB3 (Erbb3) and semaphorin 4D (Sema4D); ligands (such as gelsolin [Gsn] and collagen 11 alpha 2 chain [Col11a2]); and classical myelin proteins (such as myelinassociated oligodendrocyte basic protein [Mobp]), among others, are coexpressed with DDR1 (Vilella et al, 2019).
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