DDR is widely expressed in

DDR1 is widely expressed in several tissues (Alves et al., 1995, Curat & Vogel, 2002, Ferri et al., 2004, Hou et al., 2001, Mohan et al., 2001, Sakamoto et al., 2001, Tanaka et al., 1998) including the mouse (Bhatt et al., 2000, Franco-Pons et al., 2009, Sanchez et al., 1994, Seo et al., 2008, Zerlin et al., 1993) and human brain (Roig et al., 2007, Yamanaka et al., 2006, Weiner et al., 2000). Alternative splicing of the DDR1 gene generates 5 different isoforms (suffixed a–e), some of which possess deletions of the juxtamembrane or kinase domains. Notably, the longest isoform (DDR1c) was originally identified in a human fetal brain library (Alves et al., 1995). In mice, expression of DDR1 in early neurodevelopmental stages is confined to several areas in which neurogenesis is occurring (Franco-Pons et al., 2006, Zerlin et al., 1993), and elongation of cerebellar granules cell 4716 sale during neurodevelopment is DDR1-dependent (Bhatt et al., 2000). Postnatally, however, there in an increase in DDR1 expression detected in oligodendrocytes, but not in neurons (Franco-Pons et al., 2006, Sanchez et al., 1994). Furthermore, in an experimental mouse model of demyelination–remyelination induced by oral administration of cuprizone, DDR1 expression is up regulated in oligodendrocytes during the remyelination period (Franco-Pons et al., 2009). However, there is a paucity of detailed data on the expression of DDR1 in the human brain. The present study examines the expression pattern of DDR1 mRNA and protein in post-mortem samples of the human cerebral cortex.
Results
Discussion The most relevant overall finding was that DDR1 is present in myelin and is probably synthesized by oligodendrocytes. This result was supported by three different approaches. First, we detected presence of DDR1 mRNA in myelin by ISH. Second, the pattern of DDR1 immunostaining using an antibody against the C-terminal domain of the receptor is indistinguishable from, and co-localized with, MBP. Finally, we found by RT-qPCR a strong positive association between the expression levels of DDR1 and the expression levels of MAG and OLIG2 suggesting that the three proteins are expressed in oligodendrocytes. OLIG2 is a transcription factor implicated in oligodendrocyte cell fate determination and maturation (Ligon et al., 2006), whereas MAG is a glycoprotein synthesized by mature oligodendrocytes that has been implicated in the formation and maintenance of the myelin sheaths (Schachner and Bartsch, 2000). The specific role of DDR1 in myelin cannot be elucidated from our results, although we can speculate about several possible functions. First, DDR1 may participate in oligodendrocyte process outgrowth. Processes are snail-like extensions of the oligodendrocyte cytoplasmic membrane, each of which forms a segment of sheathing around an axon. A recent study demonstrated an association between DDR1 and non-muscle myosin heavy chain IIA (NMHC-IIA), which regulates fibroblast cell spreading and motility (Huang et al., 2009). Oligodendrocytes also express NMHC-IIA, which has been shown to regulate process formation (Song et al., 2001). Therefore, DDR1 anchored in the plasma membrane of oligodendrocyte processes may bind to NMHC-IIA and assemble to filaments once activated by an external stimulus (for instance, collagen). From this initial contact, the oligodendrocyte process would be promoted to extend further. Second, DDR1 could participate in axon–oligodendrocyte contact, which is important in commencing the ensheathment. Third, DDR1 may be involved in the oligodendrocyte–oligodendrocyte plasma membrane interactions, which are important in the myelin compacting process.