The vasculature is important for providing

The vasculature is important for providing a neurogenic niche for stem/progenitor cells and neuroblasts in the V-SVZ under physiological (Shen et al., 2008; Tavazoie et al., 2008; Mirzadeh et al., 2008) and post-stroke (Zhang et al., 2014) conditions. In addition, vascular endothelial cells produce various diffusible signaling molecules that attract and promote the migration of V-SVZ-derived neuroblasts toward a stroke-injured area (Grade et al., 2013; Snapyan et al., 2009; Won et al., 2013). However, the function and molecular basis of the blood vessel-guided neuronal migration are unclear. β1-class integrins are transmembrane receptors for several extracellular matrix (ECM) proteins, and β1-class integrin-mediated ECM adhesion is involved in the migration of various cell types (Huttenlocher and Horwitz, 2011). The vasculature in the Plerixafor is ensheathed by several ECM proteins, including laminin, which is a major ligand for several β1-class integrins (Hallmann et al., 2005). Neuroblasts generated in the adult V-SVZ express β1 integrin, which is necessary for their chain formation during RMS migration (Belvindrah et al., 2007; Emsley and Hagg, 2003; Kokovay et al., 2012). However, how β1 integrin promotes vessel-associated neuronal migration toward injured areas is unknown. Here, using a neuroblast-specific β1 integrin gene knockout mouse line, we show that laminin-β1 integrin signaling enables neuroblasts to form chains and migrate efficiently along blood vessels in the post-stroke brain.
Materials and Methods
Results
Discussion In addition to the migration of V-SVZ-derived neuroblasts toward the injured site in the post-stroke brain, as we and others have previously reported (Kojima et al., 2010; Ohab et al., 2006; Yamashita et al., 2006), vasculature-guided migration occurs in various tissues and situations, such as in lympathic endothelial cells and oligodendrocyte precursors during development (Bussmann et al., 2010; Tsai et al., 2016), Schwann cells in peripheral nerve regeneration (Cattin et al., 2015), and tumor cells in the brain (Farin et al., 2006; Lugassy and Barnhill, 2007). However, the molecular mechanisms for these cells\' adhesion to and migration along blood vessels are unknown. Here we demonstrated that neuroblast-expressed β1-class integrins, receptor proteins that form heterodimers with multiple α subunits to bind various ECM proteins, are required for the neuroblasts\' blood vessel-guided migration. We found that deleting β1 integrin specifically in neuroblasts affected their morphology and migration speed on laminin-coated materials, suggesting that the laminin on blood vessels functions as a ligand to control the migration of β1 integrin-expressing neuroblasts. In future studies, it will be important to examine whether the integrin-mediated mechanism we discovered in V-SVZ-derived neuroblasts also acts in other cells as a general regulator of vasculature-guided migration. V-SVZ-derived neuroblasts exhibit saltatory movement, with alternating resting and migratory phases (Wichterle et al., 1997). In the resting phase, a leading process is extended, and centrosome and Golgi apparatus move into it (swelling phase), followed by nuclear translocation and detachment of the rear (migratory phase) (Schaar and McConnell, 2005). During migration on a laminin-coated dish, β1 integrin gene deletion still allowed the leading process extension and swelling to proceed normally, but impaired the stable attachment of neuroblasts to the substrate and the initiation/promotion of nuclear translocation, leading to an increased resting phase and decreased migration speed (Fig. 3). Similar defects were observed in β1 integrin-deficient neuroblasts migrating along blood vessels in living brain slices (Fig. 2). These findings suggest that the stable attachment of neurons to a laminin-containing scaffold mediated by neuronal β1 integrin facilitates the somal translocation processes such as anterior movement of the nucleus and actomyosin-mediated contraction of the rear.