Article abstract


Nature Cell Biology 12, 31 - 40 (2010)
Published online: 13 December 2009 | doi:10.1038/ncb2001

Orphan nuclear receptor TLX activates Wnt/β-catenin signalling to stimulate neural stem cell proliferation and self-renewal

Qiuhao Qu1,6, Guoqiang Sun1,6, Wenwu Li1,7, Su Yang1,2,7, Peng Ye1,7, Chunnian Zhao1, Ruth T. Yu3, Fred H. Gage4, Ronald M. Evans3,5 & Yanhong Shi1,2


The nuclear receptor TLX (also known as NR2E1) is essential for adult neural stem cell self-renewal; however, the molecular mechanisms involved remain elusive. Here we show that TLX activates the canonical Wnt/β-catenin pathway in adult mouse neural stem cells. Furthermore, we demonstrate that Wnt/β-catenin signalling is important in the proliferation and self-renewal of adult neural stem cells in the presence of epidermal growth factor and fibroblast growth factor. Wnt7a and active β-catenin promote neural stem cell self-renewal, whereas the deletion of Wnt7a or the lentiviral transduction of axin, a β-catenin inhibitor, led to decreased cell proliferation in adult neurogenic areas. Lentiviral transduction of active β-catenin led to increased numbers of type B neural stem cells in the subventricular zone of adult brains, whereas deletion of Wnt7a or TLX resulted in decreased numbers of neural stem cells retaining bromodeoxyuridine label in the adult brain. Both Wnt7a and active β-catenin significantly rescued a TLX (also known as Nr2e1) short interfering RNA-induced deficiency in neural stem cell proliferation. Lentiviral transduction of an active β-catenin increased cell proliferation in neurogenic areas of TLX-null adult brains markedly. These results strongly support the hypothesis that TLX acts through the Wnt/β-catenin pathway to regulate neural stem cell proliferation and self-renewal. Moreover, this study suggests that neural stem cells can promote their own self-renewal by secreting signalling molecules that act in an autocrine/paracrine mode.

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  1. Department of Neurosciences, Center for Gene Expression and Drug Discovery, 1500 E. Duarte Road, Duarte, California 91010, USA.
  2. Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, California 91010, USA.
  3. Gene Expression Laboratory, La Jolla, California 92037, USA.
  4. Laboratory of Genetics, La Jolla, California 92037, USA.
  5. Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
  6. These authors contributed equally to this work.
  7. These authors contributed equally to this work.

Correspondence to: Yanhong Shi1,2 e-mail: yshi@coh.org



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