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EGF-Induced Expansion of Migratory Cells in the Rostral Migratory Stream

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EGF-Induced Expansion of Migratory Cells in the Rostral Migratory Stream EGF-Induced Expansion of Migratory Cells in the Rostral Migratory Stream Olle R. Lindberg.,A˚ sa Persson., Anke Brederlau, Aidin Shabro, Hans Georg Kuhn* Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden Abstract The presence of neural stem cells in the adult brain is currently widely accepted and efforts are made to harness the regenerative potential of these cells. The dentate gyrus of the hippocampal formation, and the subventricular zone (SVZ) of the anterior lateral ventricles, are considered the main loci of adult neurogenesis. The rostral migratory stream (RMS) is the structure funneling SVZ progenitor cells through the forebrain to their final destination in the olfactory bulb. Moreover, extensive proliferation occurs in the RMS. Some evidence suggest the presence of stem cells in the RMS, but these cells are few and possibly of limited differentiation potential. We have recently demonstrated the specific expression of the cytoskeleton linker protein radixin in neuroblasts in the RMS and in oligodendrocyte progenitors throughout the brain. These cell populations are greatly altered after intracerebroventricular infusion of epidermal growth factor (EGF). In the current study we investigate the effect of EGF infusion on the rat RMS. We describe a specific increase of radixin+/Olig2+ cells in the RMS. Negative for NG2 and CNPase, these radixin+/Olig2+ cells are distinct from typical oligodendrocyte progenitors. The expanded Olig2+ population responds rapidly to EGF and proliferates after only 24 hours along the entire RMS, suggesting local activation by EGF throughout the RMS rather than migration from the SVZ. In addition, the radixin+/ Olig2+ progenitors assemble in chains in vivo and migrate in chains in explant cultures, suggesting that they possess migratory properties within the RMS. In summary, these results provide insight into the adaptive capacity of the RMS and point to an additional stem cell source for future brain repair strategies. Citation: Lindberg OR, Persson A˚, Brederlau A, Shabro A, Kuhn HG (2012) EGF-Induced Expansion of Migratory Cells in the Rostral Migratory Stream. PLoS ONE 7(9): e46380. doi:10.1371/journal.pone.0046380 Editor: Andreas Androutsellis-Theotokis, Universita¨tsklinikum Carl Gustav Carus an der Technischen Universita¨t Dresden, Germany Received July 8, 2012; Accepted August 29, 2012; Published September 28, 2012 Copyright: ß 2012 Lindberg et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by grants from the Swedish Medical Research Council (VR-M 2011-3113), the Swedish Childhood Cancer Foundation (PROJ10/ 044 and NBCNSDoktBidr09/007, Va¨stra Go¨taland regional funds for biomedical research (ALFGBG-146341), The Swedish Parkinson’s Disease Association, Stiftelsen Wilhelm och Martina Lundgrens Vetenskapsfond, Rune oct Ulla Amlo¨vs Stiftelse, Stiftelsen Edit Jacobsons Donationsfond and Stroke-Riksfo¨rbundet. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: [email protected] . These authors contributed equally to this work. Introduction intercellular adhesion molecules and integrins [10–13]. We have recently characterized the expression of ERM proteins in the adult Neurogenesis persists in two distinct niches in the adult brain; brain [14]. In the RMS, radixin was expressed in neuroblasts and the dentate gyrus of the hippocampal formation and the oligodendrocyte progenitors. Evidence is emerging that the RMS subventricular zone (SVZ) of the forebrain [1]. The SVZ supplies is more than a migratory pathway, giving rise to new cells along its new cells to the olfactory bulb (OB) via the rostral migratory entire stretch. Apart from proliferating migratory neuroblasts, the stream (RMS) which stretches across the entire forebrain [2]. The RMS has been suggested to house multipotent neural stem cells, RMS is derived from the wall of the collapsed embryonic olfactory generating both neurons and glia [15,16]. Whether the RMS is a ventricle and is structurally more similar to the SVZ than to the mere tube for channeling cells or a neurogenic niche as active as brain tissue it passes through [3,4]. The unique composition of the the SVZ makes a significant difference for putative therapeutic RMS includes cell type-specific expression of proteins, such as paradigms using the RMS as a stem cell reservoir. Epidermal polysialylated neural cell adhesion molecule (PSA-NCAM), growth factor (EGF) is a mitogen involved in regulating neural integrins and tenascin C, which promote cell-cell and cell-matrix stem cell proliferation and fate determination [17–19]. In the interactions in the RMS [5–7]. In addition, microtubule-associat- SVZ, increased EGFR signaling reduces neurogenesis in favor of ed proteins, such as Doublecortin (DCX), are indispensable for oligodendrogenesis [20]. The EGF induced oligodendrocyte maintaining a bipolar morphology and for nuclear translocation progenitors are highly migratory and able to remyelinate injured during neuroblast migration [8,9]. The transduction of extracel- white matter [21]. Commitment to the oligodendrocyte lineage is lular signals to intracellular cytoskeletal responses is important thought to reduce neuroblast differentiation of neural stem cells, during RMS migration and may be mediated by the cytoskeleton leading to a decrease of migrating neuroblasts in the SVZ and the linker proteins of the ERM (ezrin, radixin, and moesin) family. RMS [22,23]. Previous studies showed reduced numbers of The ERM proteins regulate cellular morphology, including axonal neuroblasts in the SVZ and RMS after EGF treatment; however, outgrowth and motility, through their ability to connect the actin to our knowledge, a detailed description of the RMS following cytoskeleton to transmembrane protein complexes, such as EGF treatment has not yet been performed. Considering that both PLOS ONE | www.plosone.org 1 September 2012 | Volume 7 | Issue 9 | e46380 EGF-Induced Migratory Cells in the RMS neuroblasts and oligodendrocyte progenitors of the neurogenic primers we used an initial cycle of 15 min at 95uC, followed by niches express radixin, we aimed at tracking changes in radixin- repeated cycles of 94, 55, and 72uC (40 in total). A final continuous expressing cells in the RMS after intraventricular infusion of EGF. fluorescence reading at descending temperatures (melting curve) Our results show a substantial increase of a migratory oligoden- starting at 95uC was acquired to ensure proper primer drocyte progenitor cell population in the RMS, expressing radixin, functionality and to exclude primer-dimer formation. Fold- in response to EGF stimulation. changes were calculated using Cq and the DDCq method normalizing against two reference genes (GAPDH and b-actin) Materials and Methods according to Vandesompele et al. [24], described in detail in Lindberg et al. [19]. Ethics statement All animal work was conducted according to European and Immunohistochemistry Swedish animal welfare regulations and approved by the The sections were washed in Tris-buffered saline (TBS). For all Gothenburg committee of the Swedish Animal Welfare Agency immunostainings where rabbit a-radixin or mouse a-radixin were (application no. 145/10 and 32/11). used, the washing step was followed by antigen retrieval in 0.01 M sodium citrate pH6 at 97u for 20 minutes. Sections used for BrdU Surgery and tissue preparation immunofluorescence were treated with 2 M HCl for 30 minutes at Male Wistar rats, 7–8 weeks old, with an average weight of room temperature or 37uC followed by neutralization in 0.1 M 221614 grams were used in the study. All surgeries were borate buffer. All sections were blocked for 1 h in TBS with 3% performed under ketamine (33 mg/mL Ketalar, Pfizer) and donkey serum and 0.1% Triton-X (0.2% for radixin antibodies) at xylazine (6.67 mg/mL Rompun, Bayer Healthcare AG) anesthe- room temperature, prior to primary antibody incubation. Primary sia, and all efforts were made to minimize suffering. The animals antibody incubation (for antibodies and concentrations see were divided into six groups receiving either vehicle (artificial Table 1.) was performed at 4uC for 24–72 h followed by washing cerebrospinal fluid, aCSF) or EGF (360 ng/day), for 1, 7, or 14 in TBS. Secondary antibody incubation was performed at room days. The surgeries were performed as described in Lindberg et al temperature for 2 h. The following secondary antibodies were [19]. Briefly, the minipump (Model 1002; Alzet-Durect) and used; CF555 donkey (Dk) a-rabbit IgG, CF555 Dk a-goat IgG, infusion cannula (Brain Infusion Kit 2; Alzet-Durect) were filled CF633 Dk a-goat IgG, CF488 Dk a-mouse IgG (Biotium), Alexa and primed by incubation in sterile PBS at 37uC for 24 h, to Dk a-rabbit 488, Alexa Dk a-rat 488 (Molecular Probes). ToPro3 ensure no lag time in delivery after implantation. The pumps were or YoPro1 were used as nuclear stains (Molecular Probes). After inserted intracerebroventricularly using a stereotax (David Kopf secondary antibody incubation, the sections were washed in TBS and Stoelting Co). All animals received three intraperitoneal
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