Cell migration and proliferation in postnatal murine subventricular zone neurogenesis: Roles of the epidermal growth factor receptor and dopamine receptor 3

The postnatal subventricular zone (SVZ) is one of the two largest neurogenic areas in postnatal brains and it draws much attention due to the possibility of intrinsic brain repair. Stem cells in this special area generate transit amplifying progenitor cells that in turn produce neuroblasts migrating to the olfactory bulb (OB) and differentiating into interneurons throughout life. I mainly focused on migration and proliferation to understand this on-going neurogenesis in the SVZ. First, I described motility of SVZ neuroblasts using two-photon time-lapse imaging on GFP+ reporter mice (Chapter 2). I found that migratory morphology was not predictive of cell motility and there are multiple different motility patterns within migratory population. Next, combination of static cell tracing and two-photon time-lapse imaging identified that stem and progenitor cells are stationary whereas neuroblasts are motile (Chapter 3). In search for migrating stem and progenitor cells, I unexpectedly found that epidermal growth factor receptor (EGFr), a marker for stem/progenitor cells, was weakly expressed in neuroblasts. EGFr expression and stimulation were negatively correlated with cell motility (Chapter 4). This finding suggested a novel function of EGFr regulating both cell proliferation and migration in the SVZ. Then, I turned my focus to understand the role of dopamine receptor 3 (D3R) in the postnatal SVZ proliferation, another fundamental parameter in adult neurogenesis. I found that D3R is specifically expressed in the postnatal SVZ, particularly by progenitor cell population among SVZ neurogenic subtypes. Antagonism of the D3R decreased progenitor cell proliferation in vivo and in vitro (Chapter 5). This study identified D3R as a regulator of SVZ cell proliferation. Lastly, Galectin-3 (Gal-3) is another molecule that I focus on for SVZ cell migration. Intraventricular vital dye labeling and two-photon imaging revealed that Gal-3 is indispensable in the migration (Chapter 6). In summary, this dissertation described fundamental parameters of SVZ neurogenesis and identified important regulators.