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IGF-I instructs multipotent adult neural progenitor cells to become oligodendrocytes.

Hsieh J, Aimone JB, Kaspar BK, Kuwabara T, Nakashima K, Gage FH - J. Cell Biol. (2004)

Bottom Line: Oligodendrocyte differentiation by IGF-I appears to be mediated through an inhibition of bone morphogenetic protein signaling.Furthermore, overexpression of IGF-I in the hippocampus leads to an increase in oligodendrocyte markers.These data demonstrate the existence of a single molecule, IGF-I, that can influence the fate choice of multipotent adult neural progenitor cells to an oligodendroglial lineage.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Genetics, The Salk Institute, 10010 N. Torrey Pines Road, La Jolla, CA 92037, USA.

ABSTRACT
Adult multipotent neural progenitor cells can differentiate into neurons, astrocytes, and oligodendrocytes in the mammalian central nervous system, but the molecular mechanisms that control their differentiation are not yet well understood. Insulin-like growth factor I (IGF-I) can promote the differentiation of cells already committed to an oligodendroglial lineage during development. However, it is unclear whether IGF-I affects multipotent neural progenitor cells. Here, we show that IGF-I stimulates the differentiation of multipotent adult rat hippocampus-derived neural progenitor cells into oligodendrocytes. Modeling analysis indicates that the actions of IGF-I are instructive. Oligodendrocyte differentiation by IGF-I appears to be mediated through an inhibition of bone morphogenetic protein signaling. Furthermore, overexpression of IGF-I in the hippocampus leads to an increase in oligodendrocyte markers. These data demonstrate the existence of a single molecule, IGF-I, that can influence the fate choice of multipotent adult neural progenitor cells to an oligodendroglial lineage.

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IGF-I–mediated oligodendrocyte differentiation involves an inhibition of BMP signaling. (A and B) Cells treated with 500 ng/ml IGF-I alone (A) or in combination with 50 ng/ml BMP2 (B). Cells were stained for an oligodendrocyte marker (RIP) and DAPI. (C) Quantification of RIP+ or cells treated with 500 ng/ml IGF-I alone or with different doses of BMP2 (0.05–50 ng/ml) in 4-d cultures. (D and E) Cells treated with 50 ng/ml IGF-I alone or in combination with 500 ng/ml Noggin. (F) Quantification of cells treated with different doses of IGF-I (20–1,000 ng/ml) alone (blue columns) or in conjunction with 500 ng/ml Noggin (black columns). Significant differences are indicated with an asterisk (P < 0.05, t test). (G) Cells treated with a combination of IGF-I, BMP2, and Noggin. (H) Quantification of RIP+ cells in IGF-I alone, IGF-I + BMP2, and IGF-I + BMP2 + Noggin. For G and H, concentrations are as follows: IGF-I, 500 ng/ml; BMP2, 50 ng/ml; Noggin, 500 ng/ml. Bar, 50 μm. All error bars represent SDs.
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fig5: IGF-I–mediated oligodendrocyte differentiation involves an inhibition of BMP signaling. (A and B) Cells treated with 500 ng/ml IGF-I alone (A) or in combination with 50 ng/ml BMP2 (B). Cells were stained for an oligodendrocyte marker (RIP) and DAPI. (C) Quantification of RIP+ or cells treated with 500 ng/ml IGF-I alone or with different doses of BMP2 (0.05–50 ng/ml) in 4-d cultures. (D and E) Cells treated with 50 ng/ml IGF-I alone or in combination with 500 ng/ml Noggin. (F) Quantification of cells treated with different doses of IGF-I (20–1,000 ng/ml) alone (blue columns) or in conjunction with 500 ng/ml Noggin (black columns). Significant differences are indicated with an asterisk (P < 0.05, t test). (G) Cells treated with a combination of IGF-I, BMP2, and Noggin. (H) Quantification of RIP+ cells in IGF-I alone, IGF-I + BMP2, and IGF-I + BMP2 + Noggin. For G and H, concentrations are as follows: IGF-I, 500 ng/ml; BMP2, 50 ng/ml; Noggin, 500 ng/ml. Bar, 50 μm. All error bars represent SDs.

Mentions: In the developing vertebrate telencephalon and spinal cord, BMPs have been shown to act as inhibitory signals for oligodendrocyte fate specification (Gross et al., 1996; Mekki-Dauriac et al., 2002). Additional analyses have shown that oligodendrocyte lineage progression requires an active inhibition of BMP signaling (Mabie et al., 1999; Mehler et al., 2000). To gain insight into the molecular mechanism of IGF-I–induced oligodendrocyte differentiation, we asked whether IGF-I effects are mediated through an inhibition of BMP signaling. First, we tested whether BMPs could inhibit adult neural progenitor cell oligodendrocyte differentiation. Addition of BMP2 in the presence of 500 ng/ml IGF-I resulted in a suppression of oligodendrocyte differentiation, as evidenced by a reduction in RIP+ cells compared with cultures treated with IGF-I alone (Fig. 5, A–C). Similar results were observed with BMP4 (unpublished data). This inhibition of oligodendrocyte differentiation is dose-dependent; higher concentrations of BMP2 (5–50 ng/ml) resulted in a greater suppression of oligodendrocyte differentiation, whereas partial differentiation could still be observed at lower BMP2 concentrations (0.05–0.5 ng/ml; Fig. 5 C). These results are consistent with the ability of BMPs to repress oligodendrocyte differentiation.


IGF-I instructs multipotent adult neural progenitor cells to become oligodendrocytes.

Hsieh J, Aimone JB, Kaspar BK, Kuwabara T, Nakashima K, Gage FH - J. Cell Biol. (2004)

IGF-I–mediated oligodendrocyte differentiation involves an inhibition of BMP signaling. (A and B) Cells treated with 500 ng/ml IGF-I alone (A) or in combination with 50 ng/ml BMP2 (B). Cells were stained for an oligodendrocyte marker (RIP) and DAPI. (C) Quantification of RIP+ or cells treated with 500 ng/ml IGF-I alone or with different doses of BMP2 (0.05–50 ng/ml) in 4-d cultures. (D and E) Cells treated with 50 ng/ml IGF-I alone or in combination with 500 ng/ml Noggin. (F) Quantification of cells treated with different doses of IGF-I (20–1,000 ng/ml) alone (blue columns) or in conjunction with 500 ng/ml Noggin (black columns). Significant differences are indicated with an asterisk (P < 0.05, t test). (G) Cells treated with a combination of IGF-I, BMP2, and Noggin. (H) Quantification of RIP+ cells in IGF-I alone, IGF-I + BMP2, and IGF-I + BMP2 + Noggin. For G and H, concentrations are as follows: IGF-I, 500 ng/ml; BMP2, 50 ng/ml; Noggin, 500 ng/ml. Bar, 50 μm. All error bars represent SDs.
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fig5: IGF-I–mediated oligodendrocyte differentiation involves an inhibition of BMP signaling. (A and B) Cells treated with 500 ng/ml IGF-I alone (A) or in combination with 50 ng/ml BMP2 (B). Cells were stained for an oligodendrocyte marker (RIP) and DAPI. (C) Quantification of RIP+ or cells treated with 500 ng/ml IGF-I alone or with different doses of BMP2 (0.05–50 ng/ml) in 4-d cultures. (D and E) Cells treated with 50 ng/ml IGF-I alone or in combination with 500 ng/ml Noggin. (F) Quantification of cells treated with different doses of IGF-I (20–1,000 ng/ml) alone (blue columns) or in conjunction with 500 ng/ml Noggin (black columns). Significant differences are indicated with an asterisk (P < 0.05, t test). (G) Cells treated with a combination of IGF-I, BMP2, and Noggin. (H) Quantification of RIP+ cells in IGF-I alone, IGF-I + BMP2, and IGF-I + BMP2 + Noggin. For G and H, concentrations are as follows: IGF-I, 500 ng/ml; BMP2, 50 ng/ml; Noggin, 500 ng/ml. Bar, 50 μm. All error bars represent SDs.
Mentions: In the developing vertebrate telencephalon and spinal cord, BMPs have been shown to act as inhibitory signals for oligodendrocyte fate specification (Gross et al., 1996; Mekki-Dauriac et al., 2002). Additional analyses have shown that oligodendrocyte lineage progression requires an active inhibition of BMP signaling (Mabie et al., 1999; Mehler et al., 2000). To gain insight into the molecular mechanism of IGF-I–induced oligodendrocyte differentiation, we asked whether IGF-I effects are mediated through an inhibition of BMP signaling. First, we tested whether BMPs could inhibit adult neural progenitor cell oligodendrocyte differentiation. Addition of BMP2 in the presence of 500 ng/ml IGF-I resulted in a suppression of oligodendrocyte differentiation, as evidenced by a reduction in RIP+ cells compared with cultures treated with IGF-I alone (Fig. 5, A–C). Similar results were observed with BMP4 (unpublished data). This inhibition of oligodendrocyte differentiation is dose-dependent; higher concentrations of BMP2 (5–50 ng/ml) resulted in a greater suppression of oligodendrocyte differentiation, whereas partial differentiation could still be observed at lower BMP2 concentrations (0.05–0.5 ng/ml; Fig. 5 C). These results are consistent with the ability of BMPs to repress oligodendrocyte differentiation.

Bottom Line: Oligodendrocyte differentiation by IGF-I appears to be mediated through an inhibition of bone morphogenetic protein signaling.Furthermore, overexpression of IGF-I in the hippocampus leads to an increase in oligodendrocyte markers.These data demonstrate the existence of a single molecule, IGF-I, that can influence the fate choice of multipotent adult neural progenitor cells to an oligodendroglial lineage.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Genetics, The Salk Institute, 10010 N. Torrey Pines Road, La Jolla, CA 92037, USA.

ABSTRACT
Adult multipotent neural progenitor cells can differentiate into neurons, astrocytes, and oligodendrocytes in the mammalian central nervous system, but the molecular mechanisms that control their differentiation are not yet well understood. Insulin-like growth factor I (IGF-I) can promote the differentiation of cells already committed to an oligodendroglial lineage during development. However, it is unclear whether IGF-I affects multipotent neural progenitor cells. Here, we show that IGF-I stimulates the differentiation of multipotent adult rat hippocampus-derived neural progenitor cells into oligodendrocytes. Modeling analysis indicates that the actions of IGF-I are instructive. Oligodendrocyte differentiation by IGF-I appears to be mediated through an inhibition of bone morphogenetic protein signaling. Furthermore, overexpression of IGF-I in the hippocampus leads to an increase in oligodendrocyte markers. These data demonstrate the existence of a single molecule, IGF-I, that can influence the fate choice of multipotent adult neural progenitor cells to an oligodendroglial lineage.

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