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A role for hemopexin in oligodendrocyte differentiation and myelin formation.

Morello N, Bianchi FT, Marmiroli P, Tonoli E, Rodriguez Menendez V, Silengo L, Cavaletti G, Vercelli A, Altruda F, Tolosano E - PLoS ONE (2011)

Bottom Line: In the current study, we found that the expression of the Myelin Basic Protein along with the density of myelinated fibers in the basal ganglia and in the motor and somatosensory cortex of Hx- mice were strongly reduced starting at 2 months and progressively decreased with age.Finally, in vitro experiments showed that Hx promotes OL differentiation.Thus, Hx may be considered a novel OL differentiation factor and the modulation of its expression in CNS may be an important factor in the pathogenesis of human neurodegenerative disorders.

View Article: PubMed Central - PubMed

Affiliation: Molecular Biotechnology Center, University of Turin, Turin, Italy.

ABSTRACT
Myelin formation and maintenance are crucial for the proper function of the CNS and are orchestrated by a plethora of factors including growth factors, extracellular matrix components, metalloproteases and protease inhibitors. Hemopexin (Hx) is a plasma protein with high heme binding affinity, which is also locally produced in the CNS by ependymal cells, neurons and glial cells. We have recently reported that oligodendrocytes (OLs) are the type of cells in the brain that are most susceptible to lack of Hx, as the number of iron-overloaded OLs increases in Hx- brain, leading to oxidative tissue damage. In the current study, we found that the expression of the Myelin Basic Protein along with the density of myelinated fibers in the basal ganglia and in the motor and somatosensory cortex of Hx- mice were strongly reduced starting at 2 months and progressively decreased with age. Myelin abnormalities were confirmed by electron microscopy and, at the functional level, resulted in the inability of Hx- mice to perform efficiently on the Rotarod. It is likely that the poor myelination in the brain of Hx- mice was a consequence of defective maturation of OLs as we demonstrated that the number of mature OLs was significantly reduced in mutant mice whereas that of precursor cells was normal. Finally, in vitro experiments showed that Hx promotes OL differentiation. Thus, Hx may be considered a novel OL differentiation factor and the modulation of its expression in CNS may be an important factor in the pathogenesis of human neurodegenerative disorders.

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Impaired OL development in Hx−/− mice.Brain sections of wild-type and Hx−/− mice were                            immunoreacted to discriminate between OPCs and mature OLs and OPCs and                            OLs counted as reported in Materials and                                Methods. A) Quantification of                            PDGFRα-positive cells demonstrated similar numbers of OPCs in both                            cerebral cortex and corpus callosum in Hx−/− and                            wild-type mice at P10. On the contrary, the number of CC1-positive,                            GFAP-negative mature OLs in Hx−/− mice was                            strongly reduced compared to wild-type animals at P10 and P20. Data                            represent mean ± SEM, n = 3 mice for each                            genotype. **  = P<0.01, ***                             = P<0.001. B) Maps, obtained with                            Neurolucida/Neuroexplorer, of brain sections of PDGFRα- (left) and                            CC1- (right) positive cells, respectively, in                                Hx−/− and wild-type mice at P10. Red                             =  OPCs, blue  =  mature OLs.                            Note the reduced number of mature OLs in the supragranular layer of                            cortex in Hx−/− mice. C) Representative pictures                            of CC1/GFAP double staining for CC1 (brown) and GFAP (grey) in brain                            sections of a wild-type and a Hx−/− mouse. The                            latter shows a strong reduction in the number of CC1 positive cells in                            the cortex (arrows) and in corpus callosum, CC, (arrow-heads) compared                            to wild-type animal. Bar  = 50 µm.
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pone-0020173-g005: Impaired OL development in Hx−/− mice.Brain sections of wild-type and Hx−/− mice were immunoreacted to discriminate between OPCs and mature OLs and OPCs and OLs counted as reported in Materials and Methods. A) Quantification of PDGFRα-positive cells demonstrated similar numbers of OPCs in both cerebral cortex and corpus callosum in Hx−/− and wild-type mice at P10. On the contrary, the number of CC1-positive, GFAP-negative mature OLs in Hx−/− mice was strongly reduced compared to wild-type animals at P10 and P20. Data represent mean ± SEM, n = 3 mice for each genotype. **  = P<0.01, ***  = P<0.001. B) Maps, obtained with Neurolucida/Neuroexplorer, of brain sections of PDGFRα- (left) and CC1- (right) positive cells, respectively, in Hx−/− and wild-type mice at P10. Red  =  OPCs, blue  =  mature OLs. Note the reduced number of mature OLs in the supragranular layer of cortex in Hx−/− mice. C) Representative pictures of CC1/GFAP double staining for CC1 (brown) and GFAP (grey) in brain sections of a wild-type and a Hx−/− mouse. The latter shows a strong reduction in the number of CC1 positive cells in the cortex (arrows) and in corpus callosum, CC, (arrow-heads) compared to wild-type animal. Bar  = 50 µm.

Mentions: The deficit in myelin content of Hx−/− mice might be the result of a reduction in the number of OLs or a reduction in the amount of myelin elaborated by each individual oligodendrocyte. To investigate this issue, we analyzed mature OL and OPC numbers in selected CNS areas, the cerebral somatosensory cortex and the corpus callosum, of Hx−/− and control mice at P10 and P20. OPCs were identified as PDGFRα-labeled cells, and mature OLs as CC1-positive and GFAP-negative cells. At P10, we observed a significant 40% and 30% reduction in the number of mature OLs in Hx−/− mice compared to wild-type animals in the cerebral cortex and corpus callosum, respectively, whereas OPC numbers were similar. The difference in the number of mature OLs persisted at P20 with a reduction of 40% and 15% in the cerebral cortex and corpus callosum, respectively (Figure 5A). Maps of positive cells in stained sections confirmed that Hx−/− mice were characterized by fewer mature OLs in the corpus callosum and cerebral cortex compared to wild-type mice. In the somatosensory cortex, the reduction in the number of mature OLs mainly affected the supragranular layers (Figure 5B).


A role for hemopexin in oligodendrocyte differentiation and myelin formation.

Morello N, Bianchi FT, Marmiroli P, Tonoli E, Rodriguez Menendez V, Silengo L, Cavaletti G, Vercelli A, Altruda F, Tolosano E - PLoS ONE (2011)

Impaired OL development in Hx−/− mice.Brain sections of wild-type and Hx−/− mice were                            immunoreacted to discriminate between OPCs and mature OLs and OPCs and                            OLs counted as reported in Materials and                                Methods. A) Quantification of                            PDGFRα-positive cells demonstrated similar numbers of OPCs in both                            cerebral cortex and corpus callosum in Hx−/− and                            wild-type mice at P10. On the contrary, the number of CC1-positive,                            GFAP-negative mature OLs in Hx−/− mice was                            strongly reduced compared to wild-type animals at P10 and P20. Data                            represent mean ± SEM, n = 3 mice for each                            genotype. **  = P<0.01, ***                             = P<0.001. B) Maps, obtained with                            Neurolucida/Neuroexplorer, of brain sections of PDGFRα- (left) and                            CC1- (right) positive cells, respectively, in                                Hx−/− and wild-type mice at P10. Red                             =  OPCs, blue  =  mature OLs.                            Note the reduced number of mature OLs in the supragranular layer of                            cortex in Hx−/− mice. C) Representative pictures                            of CC1/GFAP double staining for CC1 (brown) and GFAP (grey) in brain                            sections of a wild-type and a Hx−/− mouse. The                            latter shows a strong reduction in the number of CC1 positive cells in                            the cortex (arrows) and in corpus callosum, CC, (arrow-heads) compared                            to wild-type animal. Bar  = 50 µm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3102107&req=5

pone-0020173-g005: Impaired OL development in Hx−/− mice.Brain sections of wild-type and Hx−/− mice were immunoreacted to discriminate between OPCs and mature OLs and OPCs and OLs counted as reported in Materials and Methods. A) Quantification of PDGFRα-positive cells demonstrated similar numbers of OPCs in both cerebral cortex and corpus callosum in Hx−/− and wild-type mice at P10. On the contrary, the number of CC1-positive, GFAP-negative mature OLs in Hx−/− mice was strongly reduced compared to wild-type animals at P10 and P20. Data represent mean ± SEM, n = 3 mice for each genotype. **  = P<0.01, ***  = P<0.001. B) Maps, obtained with Neurolucida/Neuroexplorer, of brain sections of PDGFRα- (left) and CC1- (right) positive cells, respectively, in Hx−/− and wild-type mice at P10. Red  =  OPCs, blue  =  mature OLs. Note the reduced number of mature OLs in the supragranular layer of cortex in Hx−/− mice. C) Representative pictures of CC1/GFAP double staining for CC1 (brown) and GFAP (grey) in brain sections of a wild-type and a Hx−/− mouse. The latter shows a strong reduction in the number of CC1 positive cells in the cortex (arrows) and in corpus callosum, CC, (arrow-heads) compared to wild-type animal. Bar  = 50 µm.
Mentions: The deficit in myelin content of Hx−/− mice might be the result of a reduction in the number of OLs or a reduction in the amount of myelin elaborated by each individual oligodendrocyte. To investigate this issue, we analyzed mature OL and OPC numbers in selected CNS areas, the cerebral somatosensory cortex and the corpus callosum, of Hx−/− and control mice at P10 and P20. OPCs were identified as PDGFRα-labeled cells, and mature OLs as CC1-positive and GFAP-negative cells. At P10, we observed a significant 40% and 30% reduction in the number of mature OLs in Hx−/− mice compared to wild-type animals in the cerebral cortex and corpus callosum, respectively, whereas OPC numbers were similar. The difference in the number of mature OLs persisted at P20 with a reduction of 40% and 15% in the cerebral cortex and corpus callosum, respectively (Figure 5A). Maps of positive cells in stained sections confirmed that Hx−/− mice were characterized by fewer mature OLs in the corpus callosum and cerebral cortex compared to wild-type mice. In the somatosensory cortex, the reduction in the number of mature OLs mainly affected the supragranular layers (Figure 5B).

Bottom Line: In the current study, we found that the expression of the Myelin Basic Protein along with the density of myelinated fibers in the basal ganglia and in the motor and somatosensory cortex of Hx- mice were strongly reduced starting at 2 months and progressively decreased with age.Finally, in vitro experiments showed that Hx promotes OL differentiation.Thus, Hx may be considered a novel OL differentiation factor and the modulation of its expression in CNS may be an important factor in the pathogenesis of human neurodegenerative disorders.

View Article: PubMed Central - PubMed

Affiliation: Molecular Biotechnology Center, University of Turin, Turin, Italy.

ABSTRACT
Myelin formation and maintenance are crucial for the proper function of the CNS and are orchestrated by a plethora of factors including growth factors, extracellular matrix components, metalloproteases and protease inhibitors. Hemopexin (Hx) is a plasma protein with high heme binding affinity, which is also locally produced in the CNS by ependymal cells, neurons and glial cells. We have recently reported that oligodendrocytes (OLs) are the type of cells in the brain that are most susceptible to lack of Hx, as the number of iron-overloaded OLs increases in Hx- brain, leading to oxidative tissue damage. In the current study, we found that the expression of the Myelin Basic Protein along with the density of myelinated fibers in the basal ganglia and in the motor and somatosensory cortex of Hx- mice were strongly reduced starting at 2 months and progressively decreased with age. Myelin abnormalities were confirmed by electron microscopy and, at the functional level, resulted in the inability of Hx- mice to perform efficiently on the Rotarod. It is likely that the poor myelination in the brain of Hx- mice was a consequence of defective maturation of OLs as we demonstrated that the number of mature OLs was significantly reduced in mutant mice whereas that of precursor cells was normal. Finally, in vitro experiments showed that Hx promotes OL differentiation. Thus, Hx may be considered a novel OL differentiation factor and the modulation of its expression in CNS may be an important factor in the pathogenesis of human neurodegenerative disorders.

Show MeSH
Related in: MedlinePlus