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Molecular and Cellular Biology, October 2007, p. 6706-6717, Vol. 27, No. 19
0270-7306/07/$08.00+0     doi:10.1128/MCB.01225-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Deletion of Shp2 in the Brain Leads to Defective Proliferation and Differentiation in Neural Stem Cells and Early Postnatal Lethality{triangledown} ,{dagger}

Yuehai Ke,1,{ddagger} Eric E. Zhang,1,2,{ddagger} Kazuki Hagihara,1,{ddagger} Dongmei Wu,1 Yuhong Pang,1 Rüdiger Klein,3 Tom Curran,4 Barbara Ranscht,1 and Gen-Sheng Feng1,2*

Burnham Institute for Medical Research, 10901 N. Torrey Pines Rd., La Jolla, California 92037,1 Molecular Pathology Graduate Program, University of California—San Diego, La Jolla, California 92093,2 Department of Molecular Neurobiology, Max Planck Institute of Neurobiology, 82152 Martinsried, Germany,3 Children's Hospital of Philadelphia, 517 Abramson Research Center, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania 19104-43184

Received 9 July 2007/ Accepted 16 July 2007

The intracellular signaling controlling neural stem/progenitor cell (NSC) self-renewal and neuronal/glial differentiation is not fully understood. We show here that Shp2, an introcellular tyrosine phosphatase with two SH2 domains, plays a critical role in NSC activities. Conditional deletion of Shp2 in neural progenitor cells mediated by Nestin-Cre resulted in early postnatal lethality, impaired corticogenesis, and reduced proliferation of progenitor cells in the ventricular zone. In vitro analyses suggest that Shp2 mediates basic fibroblast growth factor signals in stimulating self-renewing proliferation of NSCs, partly through control of Bmi-1 expression. Furthermore, Shp2 regulates cell fate decisions, by promoting neurogenesis while suppressing astrogliogenesis, through reciprocal regulation of the Erk and Stat3 signaling pathways. Together, these results identify Shp2 as a critical signaling molecule in coordinated regulation of progenitor cell proliferation and neuronal/astroglial cell differentiation.

* Corresponding author. Mailing address: Burnham Institute for Medical Research, 10901 N. Torrey Pines Rd., La Jolla, CA 92037. Phone: (858) 795-5265. Fax: (858) 713-6274. E-mail: gfeng{at}burnham.org

{triangledown} Published ahead of print on 23 July 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} Y.K., E.E.Z., and K.H. made equal contributions to this study.

Molecular and Cellular Biology, October 2007, p. 6706-6717, Vol. 27, No. 19
0270-7306/07/$08.00+0     doi:10.1128/MCB.01225-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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