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The Journal of Neuroscience, November 14, 2007, 27(46):12623-12629; doi:10.1523/JNEUROSCI.3812-07.2007

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Development/Plasticity/Repair
Dynamic Contribution of Nestin-Expressing Stem Cells to Adult Neurogenesis

Diane C. Lagace,¹ Mary C. Whitman,² Michele A. Noonan,¹ Jessica L. Ables,¹ Nathan A. DeCarolis,¹ Amy A. Arguello,¹ Michael H. Donovan,¹ Stephanie J. Fischer,¹ Laure A. Farnbauch,¹ Robert D. Beech,³ Ralph J. DiLeone,³ Charles A. Greer,^2,4 Chitra D. Mandyam,⁵ and Amelia J. Eisch¹

¹Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9070, Departments of ²Neurobiology, ³Psychiatry, and ⁴Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06520, and ⁵Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California 92037

Correspondence should be addressed to Dr. Amelia J. Eisch, Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390-9070. Email: amelia.eisch{at}utsouthwestern.edu

Understanding the fate of adult-generated neurons and the mechanisms that influence them requires consistent labeling and tracking of large numbers of stem cells. We generated a nestin-CreER^T2/R26R-yellow fluorescent protein (YFP) mouse to inducibly label nestin-expressing stem cells and their progeny in the adult subventricular zone (SVZ) and subgranular zone (SGZ). Several findings show that the estrogen ligand tamoxifen (TAM) specifically induced recombination in stem cells and their progeny in nestin-CreER^T2/R26R-YFP mice: 97% of SGZ stem-like cells (GFAP/Sox2 with radial glial morphology) expressed YFP; YFP+ neurospheres could be generated in vitro after recombination in vivo, and maturing YFP+ progeny were increasingly evident in the olfactory bulb (OB) and dentate gyrus (DG) granule cell layer. Revealing an unexpected regional dissimilarity in adult neurogenesis, YFP+ cells accumulated up to 100 d after TAM in the OB, but in the SGZ, YFP+ cells reached a plateau 30 d after TAM. In addition, most SVZ and SGZ YFP+ cells became neurons, underscoring a link between nestin and neuronal fate. Finally, quantification of YFP+ cells in nestin-CreER^T2/R26R-YFP mice allowed us to estimate, for example, that stem cells and their progeny contribute to no more than 1% of the adult DG granule cell layer. In addition to revealing the dynamic contribution of nestin-expressing stem cells to adult neurogenesis, this work highlights the utility of the nestin-CreER^T2/R26R-YFP mouse for inducible gene ablation in stem cells and their progeny in vivo in the two major regions of adult neurogenesis.

Key words: dentate gyrus; subgranular zone; subventricular zone; rostral migratory stream; olfactory bulb; tamoxifen

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Received Aug. 21, 2007; revised Sept. 24, 2007; accepted Sept. 27, 2007.

Correspondence should be addressed to Dr. Amelia J. Eisch, Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390-9070. Email: amelia.eisch{at}utsouthwestern.edu

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