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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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Proposed model for the role of IGFs in multipotent neural progenitor cell fate specification: oligodendroglial and neuronal fate commitment at the expense of astroglial fates? (A) BMP signaling has been shown to stimulate astroglial differentiation and inhibit neuronal and oligodendroglial differentiation. (B) Activation of the IGF-I receptor on multipotent neural progenitor cells by IGFs leads to the up-regulation of Noggin, Smad6, and Smad7. Because Noggin, Smad6, and Smad7 inhibit BMP signaling, the net effects of IGF signaling are a block in astrocyte differentiation and an induction of neuronal and oligodendroglial differentiation. Alternatively, IGF-instructive effects on oligodendrocyte differentiation could occur in a Noggin/Smad6, Smad7-independent pathway.
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fig8: Proposed model for the role of IGFs in multipotent neural progenitor cell fate specification: oligodendroglial and neuronal fate commitment at the expense of astroglial fates? (A) BMP signaling has been shown to stimulate astroglial differentiation and inhibit neuronal and oligodendroglial differentiation. (B) Activation of the IGF-I receptor on multipotent neural progenitor cells by IGFs leads to the up-regulation of Noggin, Smad6, and Smad7. Because Noggin, Smad6, and Smad7 inhibit BMP signaling, the net effects of IGF signaling are a block in astrocyte differentiation and an induction of neuronal and oligodendroglial differentiation. Alternatively, IGF-instructive effects on oligodendrocyte differentiation could occur in a Noggin/Smad6, Smad7-independent pathway.

Mentions: We hypothesized that oligodendrocyte differentiation of multipotent adult neural progenitor cells might use similar mechanisms as oligodendrocyte progenitors derived from the embryonic brain and spinal cord, and that IGF-I induction of oligodendrocyte differentiation might involve an inhibition of BMP signaling. Our data suggest that BMPs can repress IGF-I–induced oligodendrocyte differentiation from adult neural progenitor cells. Furthermore, addition of Noggin together with lower concentrations of IGF-I results in a greater percentage of cells that differentiate into oligodendrocytes compared with IGF-I alone, suggesting that IGF-I induction of oligodendrocyte differentiation involves the activation of BMP antagonists such as Noggin. This finding, together with the observation that there is an up-regulation of Noggin, Smad6, and Smad7 with IGF-I treatment, further reinforces the role of IGF-I in the inhibition of BMP signaling to promote oligodendrocyte differentiation. A proposed model is shown in Fig. 8. BMP signaling has been shown to alter the fate of neural progenitor cells by stimulating astroglial differentiation while inhibiting neuronal and oligodendroglial differentiation (Fig. 8 A; Mehler et al., 1997; Mabie et al., 1999; Nakashima et al., 2001). IGFs (IGF-I and -II) and/or insulin activate IGF-I receptors located on multipotent neural progenitor cells, which leads to the up-regulation of BMP antagonists such as Noggin, Smad6, and Smad7. Because Noggin, Smad6, and Smad7 inhibit BMP signaling, the net effects of IGF signaling are a decrease or absence of astrocyte differentiation and an increase in neuronal and oligodendroglial differentiation (Fig. 8 B). Future analyses are needed to determine whether all of the IGF-instructive effects on oligodendrocyte differentiation occur through an inhibition of BMP signaling, or if IGFs can directly promote oligodendroglial lineage commitment in a Noggin/Smad6, Smad7-independent manner.


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)

Proposed model for the role of IGFs in multipotent neural progenitor cell fate specification: oligodendroglial and neuronal fate commitment at the expense of astroglial fates? (A) BMP signaling has been shown to stimulate astroglial differentiation and inhibit neuronal and oligodendroglial differentiation. (B) Activation of the IGF-I receptor on multipotent neural progenitor cells by IGFs leads to the up-regulation of Noggin, Smad6, and Smad7. Because Noggin, Smad6, and Smad7 inhibit BMP signaling, the net effects of IGF signaling are a block in astrocyte differentiation and an induction of neuronal and oligodendroglial differentiation. Alternatively, IGF-instructive effects on oligodendrocyte differentiation could occur in a Noggin/Smad6, Smad7-independent pathway.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2171962&req=5

fig8: Proposed model for the role of IGFs in multipotent neural progenitor cell fate specification: oligodendroglial and neuronal fate commitment at the expense of astroglial fates? (A) BMP signaling has been shown to stimulate astroglial differentiation and inhibit neuronal and oligodendroglial differentiation. (B) Activation of the IGF-I receptor on multipotent neural progenitor cells by IGFs leads to the up-regulation of Noggin, Smad6, and Smad7. Because Noggin, Smad6, and Smad7 inhibit BMP signaling, the net effects of IGF signaling are a block in astrocyte differentiation and an induction of neuronal and oligodendroglial differentiation. Alternatively, IGF-instructive effects on oligodendrocyte differentiation could occur in a Noggin/Smad6, Smad7-independent pathway.
Mentions: We hypothesized that oligodendrocyte differentiation of multipotent adult neural progenitor cells might use similar mechanisms as oligodendrocyte progenitors derived from the embryonic brain and spinal cord, and that IGF-I induction of oligodendrocyte differentiation might involve an inhibition of BMP signaling. Our data suggest that BMPs can repress IGF-I–induced oligodendrocyte differentiation from adult neural progenitor cells. Furthermore, addition of Noggin together with lower concentrations of IGF-I results in a greater percentage of cells that differentiate into oligodendrocytes compared with IGF-I alone, suggesting that IGF-I induction of oligodendrocyte differentiation involves the activation of BMP antagonists such as Noggin. This finding, together with the observation that there is an up-regulation of Noggin, Smad6, and Smad7 with IGF-I treatment, further reinforces the role of IGF-I in the inhibition of BMP signaling to promote oligodendrocyte differentiation. A proposed model is shown in Fig. 8. BMP signaling has been shown to alter the fate of neural progenitor cells by stimulating astroglial differentiation while inhibiting neuronal and oligodendroglial differentiation (Fig. 8 A; Mehler et al., 1997; Mabie et al., 1999; Nakashima et al., 2001). IGFs (IGF-I and -II) and/or insulin activate IGF-I receptors located on multipotent neural progenitor cells, which leads to the up-regulation of BMP antagonists such as Noggin, Smad6, and Smad7. Because Noggin, Smad6, and Smad7 inhibit BMP signaling, the net effects of IGF signaling are a decrease or absence of astrocyte differentiation and an increase in neuronal and oligodendroglial differentiation (Fig. 8 B). Future analyses are needed to determine whether all of the IGF-instructive effects on oligodendrocyte differentiation occur through an inhibition of BMP signaling, or if IGFs can directly promote oligodendroglial lineage commitment in a Noggin/Smad6, Smad7-independent manner.

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.

Show MeSH