A Role for Hemopexin in Oligodendrocyte Differentiation and Myelin Formation

Noemi Morello,Guido Cavaletti,Lorenzo Silengo,Paola Marmiroli,Federico Tommaso Bianchi,Fiorella Altruda,Alessandro Vercelli,Virginia Rodriguez Menendez,Elisabetta Tonoli,Emanuela Tolosano,Rafael Linden

doi:10.1371/journal.pone.0020173

Noemi Morello, Guido Cavaletti + Show 9 more

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https://doi.org/10.1371/journal.pone.0020173

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Journal: PloS one	Publication Date: May 25, 2011
Citations: 73	License type: cc-by

Affiliation: University of Turin, University of Milan

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-null 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-null 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-null mice to perform efficiently on the Rotarod. It is likely that the poor myelination in the brain of Hx-null 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.

Highlights

Myelin formation in the brain occurs predominantly postnatally in well-regulated steps during which oligodendrocytes (OLs) mature and extend processes to contact and enwrap axons [1,2,3,4,5,6,7,8]
Myelin formation is critical for the proper function and maintenance of axons [9] and, on the other hand, the survival of OLs depends on their interactions with axons [10]
Histology Animals were anaesthetised with Avertin (2,2,2-tribromoethanol; Sigma-Aldrich, Milano, Italy) at a dose of 2 mg/kg body weight and transcardially perfused with 0.1 M phosphate-buffered saline (PBS), pH 7.2 followed by fixative solution (4% paraformaldehyde in PBS)

Summary

Introduction

Myelin formation in the brain occurs predominantly postnatally in well-regulated steps during which oligodendrocytes (OLs) mature and extend processes to contact and enwrap axons [1,2,3,4,5,6,7,8]. Myelin formation is critical for the proper function and maintenance of axons [9] and, on the other hand, the survival of OLs depends on their interactions with axons [10]. Finding the factors that can promote myelin formation is of major relevance for the physiological organization and function of the CNS. By using mice bearing a knock-in allele expressing beta-galactosidase instead of Hx, we demonstrated that in the CNS, Hx is produced by ependymal cells lining the ventricular system and by hippocampal neurons [17]

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