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, 58 (12), 1407-14

Control of Oligodendrocyte Generation and Proliferation by Shp2 Protein Tyrosine Phosphatase

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Control of Oligodendrocyte Generation and Proliferation by Shp2 Protein Tyrosine Phosphatase

Ying Zhu et al. Glia.

Abstract

Extracellular signals play essential roles in controlling the proliferation and differentiation of oligodendrocyte progenitor cells in the developing central nervous system. However, the intracellular pathways that transduce these extrinsic signals remain to be elucidated. In this study, we showed that conditional ablation of the nonreceptor tyrosine phosphatase Shp2 in Olig1-expressing oligodendrocyte lineage resulted in dramatic reduction in the generation and proliferation of oligodendrocyte progenitor cells in the spinal cord. Maturation and myelination of oligodendrocytes were also compromised in the Shp2 mutants. The deficits in oligodendrocyte development in Shp2 mutants nearly phenocopied those observed in PDGF-A mutants, suggesting that Shp2 is a crucial component in transducing PDGF-A signals in the control of oligodendrocyte proliferation and maturation.

Figures

Figure 1
Figure 1
Normal development of neural progenitor cells in the pMN domain and motor neurons in Shp2 mutant spinal cord. The spinal cord sections from control (A, C, E) and the mutant mice (B, D, F) at E11.5 were immunostained with anti-Olig2 (A, B), anti-Hb9 (C, D) and anti-Islet-1 (E, F). Scale bar, 100 μm.
Figure 2
Figure 2
Reduced Olig2+ cells in Shp2-Olig1Cre mutant spinal cords. (A–H) Olig2 immunofluorescent staining in the control (A–D) and mutant (E–H) spinal cords from E13.5 to P7; Scale bar, 100 μm; (I) Quantitative analysis of the number of Olig2+ cells migrating out of the ventricular zone. Olig2+ cells were counted under 10X magnification. At least 3 sections were counted for each animal at each stage (*P<0.08).
Figure 3
Figure 3
Decreased expression of PDGFR in the Shp2-Olig1Cre mutants. Spinal cord sections from E13.5 to P7 control (A–D) and mutant (E–H) animals were subjected to RNA in situ hybridization. The number of PDGFRα+ OPC cells was drastically reduced in the mutants at all stages examined. Scale bar, 100 μm.
Figure 4
Figure 4
Assays of oligodendrocyte proliferation and apoptosis in E16.5 spinal cords. A–B. Double immunofluorescent staining with anti-BrdU and anti-Olig2. Double-stained cells are represented by arrows. C–D Double immunostaining with anti-pCaspase 3 and anti-Sox10. Green and red arrowheads represent oligodendrocytes and apoptotic cells, respectively. Scale bar, 100 μm. (E) The percentage of BrdU labeled Olig2+ cell at E16.5. More than 400 Olig2-positive and BrdU/Olig2 double positive cells from 4 different sections were counted under 10X magnification (*P<0.01).
Figure 5
Figure 5
Defective oligodendrocyte migration and differentiation in the Shp2 mutants. A–B. Spinal cord sections of E16.5 embryos were subjected to MBP ISH hybridization followed by anti-Olig2 immunohistochemical staining. The ventral midline was indicated by broken lines, and arrows represented double positive cells shown in insets at the upper right corner. C–D. Spinal cord sections from P0 pups were examined for MBP expression by ISH.
Figure 6
Figure 6
Reduced oligodendrocyte differentiation in Shp2 mutants. Spinal cord sections from P7 (A, B, E, F) and P15 (C, D, G, H) mice were subjected to ISH hybridization with Mbp and Plp probes respectively. (I, J) Spinal cord sections of P7 were simultaneously immunostained with anti-Olig2 and anti-APC antibodies. (K). Percentage of APC+ mature oligodendrocytes among Olig2+ cells in the ventral white matter region (*P<0.05). (L) The Mbp expression level was examined by western blotting. Scale bars, 100 μm in A–H; 20 μm in I and J.
Figure 7
Figure 7
Reduced axonal myelination in the Shp2 mutant spinal cord at P15. The percentage of myelinated axons in the spinal cord is reduced compared to the control (C), *P<0.001. Scale bar, 5 μm.

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