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

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.

Neurons or Glia? Can SHP2 Know It All?

“…SHP2 is an appealing molecule in the context of regulation of neurogenesis and gliogenesis, because it modulates not only the neurogenic (MEK-ERK), but also the gliogenic (gp130-JAK-STAT) signaling pathways by promoting MEK-ERK signaling while simultaneously inhibiting gp130-JAK-STAT signaling, respectively (6,7,26) (Fig. 1).…”

The Protein Tyrosine Phosphatase Shp2 Is Required for the Generation of Oligodendrocyte Progenitor Cells and Myelination in the Mouse Telencephalon

“…These developmental syndromes are referred to as neuro-cardio-faciocutaneous syndromes as a result of overlapping phenotypes or "RASopathies" due to the abnormal regulation of the RAS/ MAPK pathway (Gelb and Tartaglia, 2006;Bentires-Alj et al, 2006;Tidyman and Rauen, 2009). In addition to growth, cardiovascular, and craniofacial defects, various studies have reported that nearly 50% of Noonan syndrome patients exhibit some form of neurocognitive impairment, suggesting an impact of the Shp2 GOF mutations in human brain development (Lee et Previous studies have shown a role for Shp2 in cell fate decisions by promoting neurogenesis and repressing astrogliogenesis in the developing hippocampus and cortex of the telencephalon (Gauthier et al, 2007;Ke et al, 2007). Moreover, Gauthier et al (2007) showed that germline Noonan syndrome mice (PTPN11 D61G/ϩ ) show more neurons and fewer astrocytes in the hippocampus and dorsal cortex at postnatal day 2, suggesting that Noonan syndrome mutations cause cellular brain abnormalities.…”

“…Notably, white matter regions and oligodendrocytes were not analyzed in these mice. In vitro studies have suggested different roles for Shp2 during OL proliferation and maturation (Kuo et al, 2010;Liu et al, 2011). Yet, the precise in vivo role for Shp2 or consequence of Noonan syndrome Shp2 GOF mutations during telencephalic oligodendrogenesis remains unknown.…”

S-nitrosylated SHP-2 contributes to NMDA receptor-mediated excitotoxicity in acute ischemic stroke

“…We and others have recently shown that transient activation of the ERK1/2 signaling cascade mediates prosurvival effects of SHP-2 in mouse embryonic fibroblasts and in neural progenitor cells (14,15). To determine whether SHP-2 activity functions downstream of NMDARs and affects the ERK1/2 pathway in cortical neurons, we initially used the highly selective MEK inhibitor PD098059, as MEK is the kinase that activates ERK through dual phosphorylation of threonine and tyrosine residues (35).…”

“…SHP-2 is known to localize in the cytosol and nucleus, and plays important biological functions in response to various growth factors, hormones, and cytokines (13). Recent studies have shown that activation of SHP-2 increases survival of various cell types, including neural progenitor cells and neurons, through activation of ERK1/2 (14,15). SHP-2 is thought to promote ERK signaling by dephosphorylating negative regulators of the Ras-ERK pathway, such as PAG/Cbp, Ras-GAP, or GAP-binding sites on receptor tyrosine kinases or Sprouty proteins (16)(17)(18)(19)(20).…”