Oligodendroglial differentiation induces mitochondrial genes and inhibition of mitochondrial function represses oligodendroglial differentiation
Introduction
Oligodendrocytes are responsible for myelination of the axons in the Central Nervous System (CNS). Axons are initially unmyelinated and become myelinated during development. Myelination buffers the dissipation of the action potential along the axons, and provides trophic support for neurons. Oligodendroglial precursor cells grow into immature/galactosylceramide-positive oligodendrocytes, and finally into mature, myelin-producing oligodendrocytes (Baumann and Pham-Dinh, 2001).
Crosstalk between neurons, astrocytes and oligodendrocytes is necessary for proper oligodendrocyte differentiation and myelination. Growth factors such as PDGF, FGF-2, IGF-1, NT-3 and CNTF, released by neurons and astrocytes, function to promote oligodendrocyte differentiation. Neuregulin promotes differentiation via interaction with the ErbB receptor on oligodendrocytes (reviewed in (Simons and Trajkovic, 2006)). The interaction between F3/contactin and notch also promotes oligodendrocyte maturation (Hu et al., 2003). The electrical activity of neurons and the release of leukemia inhibitory factor from astrocytes have been shown to be important for initiating myelination (Ishibashi et al., 2006).
Demyelination occurs in multiple mitochondrial diseases, including Leber’s Hereditary Optic Neuropathy (Kovacs et al., 2005), Friedreich’s ataxia (Carelli et al., 2002), MELAS (Rusanen et al., 1995), Charcot-Marie Tooth 2a, caused by a defect in mitofusin 2 (Niemann et al., 2006), and Dominant Optic Atrophy, caused by a defect in opa1 (Johnston et al., 1979). Demyelination also occurs in Periventricular Leukomalacia (PVL), as a consequence of hypoxia/ischemia (Volpe, 2008). Consistent with the observation of demyelination in the mitochondrial genetic diseases named above, a recent microarray study of five mitochondrial diseases produced the unexpected result of significant down-regulation of several transcripts involved in myelination (Cortopassi et al., 2006). These results suggest that mitochondrial functions might be required for proper oligodendrocyte differentiation and myelination. To test this idea, we microarrayed undifferentiated and differentiated rat and human oligodendroglia. We also tested the effects of mitochondrial inhibition on oligodendroglial differentiation and found differentiating cells to be particularly sensitive to rotenone.
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Materials and methods
Biochemical reagents were purchased from Sigma (St. Louis, MO), Invitrogen (Carlsbad, CA) or Bio-Rad (Hercules, CA). Microarray chips and reagents were purchased from Affymetrix (Santa Clara, CA).
Microarray analysis
We carried out four independent microarray comparisons of undifferentiated to differentiated oligodendroglia, two from primary rat cells and two from human cells lines (HOG and MO3.13), using 4–9 chips per group. We then counted those genes that were significantly altered in the same direction in at least three of the four groups. These included 559 activated and 535 inhibited genes. Thus, differentiation induced and inhibited similar numbers of transcripts (Supplementary Fig. 1).
Oligodendroglial differentiation induces mitochondrial transcripts and inhibits cell cycle transcripts
We carried out
Oligodendroglial differentiation induces cholesterologenic and mitochondrial transcripts
We microarrayed and performed gene ontology analysis on oligodendroglial precursor cells and differentiated oligodendroglia. A strong and significant induction of cholesterol-related, mitochondrial and myelination transcripts was observed with differentiation, demonstrating an intense activation of the cholesterol pathway and a requirement for mitochondrial functions. In contrast, many important cell proliferation genes, including DNA ligase 1, Cyclins B1 and D1 and cell division cycle 20 and
Acknowledgements
This work was supported by grants from the USPHS – EY12245, AG11967, AG16719, AG23311 (to G.A.C.), NS25044 (to D.P.) and National Multiple Sclerosis Society award RG3419A1/1T (to T.I.). We thank J. Nielsen and L. Hudson for sharing microarray data.
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These authors contributed equally to this work.