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The Journal of Neuroscience, February 21, 2007, 27(8):1836-1852; doi:10.1523/JNEUROSCI.5141-06.2007

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Development/Plasticity/Repair
Self-Renewing and Differentiating Properties of Cortical Neural Stem Cells Are Selectively Regulated by Basic Fibroblast Growth Factor (FGF) Signaling via Specific FGF Receptors

Dragan Maric,¹ Alessandra Fiorio Pla,^2,3 Yoong Hee Chang,¹ and Jeffery L. Barker¹

¹Laboratory of Neurophysiology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, ²Laboratory of Physiology, Department of Human and Animal Biology, University of Torino, 10123 Torino, Italy, and ³Nanostructured Interfaces and Surfaces Centre of Excellence, 10125 Torino, Italy

Correspondence should be addressed to Dragan Maric, Laboratory of Neurophysiology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Building 49, Room 2B-63, Bethesda, MD 20892. Email: maricd{at}ninds.nih.gov

Developmental processes mediating the initiation of lineage commitment from self-renewing neural stem cells (NSCs) remain mostly unclear because of the persisting ambiguity in identifying true NSCs from proliferative lineage-restricted progenitors (LRPs), which are directly or indirectly derived from NSCs. Our multilineage immunohistochemical analyses of early embryonic rat telencephalon at the onset of neurogenesis revealed clear dorsoventral gradients in the emergence of two types of neuronal progenitors (NPs) from multilineage-negative NSCs. Enumeration of NSCs using comprehensive flow cytometric analysis demonstrated that their precipitous decline in vivo involved both active differentiation into NPs and an increased propensity toward apoptosis. Both processes paralleled the dorsoventral changes in fibroblast growth factor receptor (FGFR) expressions. NSCs residing in the dorsal telencephalon coexpressed FGFR1 and FGFR3, whereas those residing in the ventral telencephalon also expressed FGFR2. NSCs exposed to basic fibroblast growth factor (bFGF) in vitro generated four stereotypical clonal expansion states: efficiently self-renewing, inefficiently self-renewing limited by apoptosis, exclusively neurogenic, and multipotential, generating up to five types of LRPs. The plasticity among these expansion states depended on ambient [bFGF], telencephalic developmental stage, and differential activation/inactivation of specific FGFRs. Coactivation of FGFR1 and FGFR3 promoted symmetrical divisions of NSCs (self-renewal), whereas inactivation of either triggered asymmetrical divisions and neurogenesis from these cells. Developmental upregulation of FGFR2 expression correlated with a shift of NSCs into a multipotential state or apoptosis. These results provide new insights regarding the roles of FGFRs in diversification of NSC properties and initiation of neural lineage-restricted differentiation.

Key words: rat; cortical; development; neural stem cells; progenitors; flow cytometry

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Received July 31, 2006; revised Nov. 27, 2006; accepted Jan. 4, 2007.

Correspondence should be addressed to Dragan Maric, Laboratory of Neurophysiology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Building 49, Room 2B-63, Bethesda, MD 20892. Email: maricd{at}ninds.nih.gov

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