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The Journal of Neuroscience, July 8, 2009, 29(27):8704-8714; doi:10.1523/JNEUROSCI.5527-08.2009

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Development/Plasticity/Repair
VEGFR-1 Regulates Adult Olfactory Bulb Neurogenesis and Migration of Neural Progenitors in the Rostral Migratory Stream In Vivo

Ina M. Wittko,^1,2 Anne Schänzer,¹ Andrey Kuzmichev,² Fabian T. Schneider,¹ Masabumi Shibuya,³ Sabine Raab,¹ and Karl H. Plate¹

¹Goethe University Medical School, Institute of Neurology (Edinger Institute), Neuroscience Center, 60528 Frankfurt am Main, Germany, ²Laboratory of Molecular Biology, National Institute of Neurological Disorders and Stroke, Porter Neuroscience Research Center, National Institutes of Health, Bethesda, Maryland 20892, and ³Department of Molecular Oncology, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8519, Japan

Correspondence should be addressed to Karl H. Plate, Goethe University Medical School, Institute of Neurology (Edinger Institute), Neuroscience Center, Heinrich-Hoffmann Strasse 7, 60528 Frankfurt am Main, Germany. Email: karl-heinz.plate{at}kgu.de

The generation of new neurons in the olfactory bulb (OB) persists into adulthood and is a multistep process that includes proliferation, fate choice, migration, survival, and differentiation. Neural precursor cells destined to form olfactory interneurons arise in the subventricular zone (SVZ) and migrate along the rostral migratory stream (RMS) to the OB. Recently, some factors classically known from their effects on the vascular system have been found to influence different steps of adult neurogenesis. In the present study, we report a modulatory function for the vascular endothelial growth factor receptor-1 (VEGFR-1) in adult olfactory neurogenesis. We identified expression of VEGFR-1 in GFAP-positive cells within regions involved in neurogenesis of the adult mouse brain. To determine functions for VEGFR-1 in adult neurogenesis, we compared neural progenitor cell proliferation, migration, and differentiation from wild-type and VEGFR-1 signaling-deficient mice (Flt-1TK^–/– mice). Our data show that VEGFR-1 signaling is involved in the regulation of proliferation of neuronal progenitor cells within the SVZ, migration along the RMS, and in neuronal differentiation and anatomical composition of interneuron subtypes within the OB. RMS migration in Flt-1TK^–/– mice was altered mainly as a result of increased levels of its ligand VEGF-A, which results in an increased phosphorylation of VEGFR-2 in neuronal progenitor cells within the SVZ and the RMS. This study reveals that proper RMS migration is dependent on endogenous VEGF-A protein.

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Received Nov. 12, 2008; revised Feb. 27, 2009; accepted May 28, 2009.

Correspondence should be addressed to Karl H. Plate, Goethe University Medical School, Institute of Neurology (Edinger Institute), Neuroscience Center, Heinrich-Hoffmann Strasse 7, 60528 Frankfurt am Main, Germany. Email: karl-heinz.plate{at}kgu.de

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