Abstract
Neurogenesis persists in the adult brain and can be regulated by a plethora of external stimuli, such as learning, memory, exercise, environment and stress1. Although newly generated neurons are able to migrate and preferentially incorporate into the neural network2,3,4,5, how these cells are molecularly regulated and whether they are required for any normal brain function are unresolved questions6. The adult neural stem cell pool is composed of orphan nuclear receptor TLX-positive cells7. Here, using genetic approaches in mice, we demonstrate that TLX (also called NR2E1) regulates adult neural stem cell proliferation in a cell-autonomous manner by controlling a defined genetic network implicated in cell proliferation and growth. Consequently, specific removal of TLX from the adult mouse brain through inducible recombination results in a significant reduction of stem cell proliferation and a marked decrement in spatial learning. In contrast, the resulting suppression of adult neurogenesis does not affect contextual fear conditioning, locomotion or diurnal rhythmic activities, indicating a more selective contribution of newly generated neurons to specific cognitive functions.
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Acknowledgements
We thank Y. Shi, H. Suh, M. Downes, M. Nelson, H. Juguilon, J. Havstad, B. Miller, R. Summers and M. Lucero for technical help; M. Tallquist and K. Lee for providing materials; R. Yu and M. Gage for editing; and S. Ganley and E. Ong for administrative assistance. C-.L.Z. is a Howard Hughes Medical Institute (HHMI) Fellow of the Life Sciences Research Foundation. R.M.E. is an Investigator of the HHMI and March of Dimes Chair in Molecular and Developmental Biology. F.H.G. is the Adler Professor of Age-Related Neurodegenerative Diseases. This work was funded through the support of the HHMI, Nuclear Receptor Signalling Atlas (NURSA), NICHD, NIGMS, the Lookout Fund, the McDonnell Foundation, the Picower Foundation and the NIH. R.M.E. acknowledges a grant from Merck.
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Supplementary Information 1
The file contains Supplementary Figures S1-S16 with Legends. (PDF 5017 kb)
Supplementary Information 2
The file contains Supplementary Data 1 analysing globally regulated genes 36 h after inducible deletion of TLX (NR2E1) in cultured adult neural stem cells. (XLS 136 kb)
Supplementary Information 3
The file contains Supplementary Data 2 analysing globally regulated genes 60 h after inducible deletion of TLX (NR2E1) in cultured adult neural stem cells. (XLS 190 kb)
Supplementary Information 4
The file contains Supplementary Data 3 analysing. genes showing changes both at 36 h and 60 h after inducible deletion of TLX (NR2E1) in cultured adult neural stem cells. (XLS 78 kb)
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Zhang, CL., Zou, Y., He, W. et al. A role for adult TLX-positive neural stem cells in learning and behaviour. Nature 451, 1004–1007 (2008). https://doi.org/10.1038/nature06562
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DOI: https://doi.org/10.1038/nature06562
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