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Increased susceptibility to ischemia-induced brain damage in transgenic mice overexpressing a dominant negative form of SHP2

YOKO AOKI^*,1, ZHIHONG HUANG, SUNU S. THOMAS, PRADEEP G. BHIDE^§, IVANA HUANG^*, MICHAEL A. MOSKOWITZ and STEVEN A. REEVES^*2

^* CNS Signaling Laboratory, Molecular Neuro-Oncology,
Stroke and Neurovascular Regulation, and
^§ Developmental Neurobiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA

²Correspondence: CNS Signaling Laboratory, Molecular Neuro-Oncology, 149 13th St., Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA. E-mail: reeves{at}helix.mgh.harvard.edu

Cell culture studies have established SH2 domain-containing protein tyrosine phosphatase-2 (SHP2) as an important factor in growth factor and cytokine-activated signaling pathways. However, the significance of SHP2 in the mammalian central nervous system (CNS) is not known since early embryonic lethality occurs in shp2 null mice. To bypass this embryonic lethality, transgenic animals containing a catalytically inactive mutant of SHP2 (SHP2-CS) under the control of a nestin intron II/thymidine kinase minimal promoter were generated. In the developing CNS of these animals, although high-level transgene expression was detected in the neuroepithelium, there was no obvious abnormality in progenitor cell proliferation or migration. In the adult brain, high-level transgene expression was detected in the subventricular zone, rostral migratory stream, dentate gyrus of hippocampus, and cerebellum. Because SHP2 function is likely important in cell survival pathways, we used a focal cerebral ischemia model to examined whether SHP2 is important during CNS injury. Ischemia-induced damage and neuronal death was found to be significantly greater in nestin-SHP2-CS mice than in wild-type littermates. These findings indicate that SHP2 is a required factor in signaling pathway(s) important for neuronal survival.—Aoki, Y., Huang, Z., Thomas, S. S., Bhide, P. G., Huang, I., Moskowitz, M. A., Reeves, S. A. Increased susceptibility to ischemia-induced brain damage in transgenic mice overexpressing a dominant negative form of SHP2.

Key Words: protein tyrosine phosphatase • cell survival • cerebral ischemia • neuron

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