1. Howard Hughes Medical Institute,
2. Gene Expression Laboratory, and,
3. Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037, USA
4. Present address: The Institute of Biosciences and Technology, 2121 W. Holcombe Boulevard, Houston, Texas 77030, USA.

Correspondence to: Fred H. Gage³Ronald M. Evans^1,2 Correspondence and requests for materials should be addressed to R.M.E. (Email: evans@salk.edu) or F.H.G. (Email: gage@salk.edu).

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 network^{2, 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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