Deletion of Shp2 in the Brain Leads to Defective Proliferation and Differentiation in Neural Stem Cells and Early Postnatal Lethality

Yuehai Ke,Tom Curran,Rüdiger Klein,Yuhong Pang,Barbara Ranscht,Gen-Sheng Feng,Dongmei Wu,Kazuki Hagihara,Eric E Zhang

doi:10.1128/mcb.01225-07

Abstract

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.

Highlights

Neural stem/progenitor cells (NSCs) are clonogenic cells capable of self-renewal and generating all neuronal and glial cell lineages
We demonstrate that Shp2 is an important player during mammalian brain development, by generating a novel mutant mouse model with Shp2 selectively deleted in neural precursor cells
Deletion of Shp2 in NSCs leads to early postnatal lethality

Summary

Introduction

Neural stem/progenitor cells (NSCs) are clonogenic cells capable of self-renewal and generating all neuronal and glial cell lineages. Epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) have been shown to induce neural fate specification in embryonic stem cells (ESCs) and potently stimulate the self-renewal capacity of NSCs in vivo and in vitro [12, 35, 37]. Transcription factors, such as the polycomb family transcriptional repressor Bmi-1, are required for NSC self-renewal [22]. Our results provide a fresh view of molecular signaling mechanisms coordinating NSC self-renewal and cell lineage specification

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Results

Conclusion