Unconjugated bilirubin restricts oligodendrocyte differentiation and axonal myelination.

Barateiro, Andreia, Miron, Veronique E., Santos, Sofia D., Relvas, João B., Fernandes, Adelaide, Ffrench-Constant, Charles ORCID: https://orcid.org/0000-0002-5621-3377 and Brites, Dora (2012) Unconjugated bilirubin restricts oligodendrocyte differentiation and axonal myelination. Molecular Neurobiology, 47 (2). pp. 632-644. ISSN 0893-7648

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High levels of serum unconjugated bilirubin (UCB) in newborns are associated with axonal damage and glial reactivity that may contribute to subsequent neurologic injury and encephalopathy (kernicterus). Impairments in myelination and white matter damage were observed at autopsy in kernicteric infants. We have recently reported that UCB reduces oligodendrocyte progenitor cell (OPC) survival in a pure OPC in vitro proliferative culture. Here, we hypothesized that neonatal hyperbilirubinemia may also impair oligodendrocyte (OL) maturation and myelination. We used an experimental model of hyperbilirubinemia that has been shown to mimic the pathophysiological conditions leading to brain dysfunction by unbound (free) UCB. Using primary cultures of OL, we demonstrated that UCB delays cell differentiation by increasing the OPC number and reducing the number of mature OL. This finding was combined with a downregulation of Olig1 mRNA levels and upregulation of Olig2 mRNA levels. Addition of UCB, prior to or during differentiation, impaired OL morphological maturation, extension of processes and cell diameter. Both conditions reduced active guanosine triphosphate (GTP)-bound Rac1 fraction. In myelinating co-cultures of dorsal root ganglia neurons and OL, UCB treatment prior to the onset of myelination decreased oligodendroglial differentiation and the number of myelinating OL, also observed when UCB was added after the onset of myelination. In both circumstances, UCB decreased the number of myelin internodes per OL, as well as the myelin internode length. Our studies demonstrate that increased concentrations of UCB compromise myelinogenesis, thereby elucidating a potential deleterious consequence of elevated UCB.

Item Type: Article
Additional Information: Funding Information: This work was supported by the strategic project PEst-OE/SAU/UI4013/2011 and PTDC/SAU-NEU/64385/2006 grants from Fundação para a Ciência e a Tecnologia (FCT), Lisbon, Portugal (to D. B.). A.B. was a recipient of a PhD fellowship (SFRH/BD/43885/2008) from FCT. SDS acknowledges POPH - QREN-Tipologia 4.2 - Promotion of scientific employment funded by the ESF and MCTES. Work in the lab of JBR was supported by project PTDC/BIA-BCM/112730/2009 from FCT. V.M. received a post-doctoral fellowship from the Multiple Sclerosis Society of Canada. The funding organization had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Uncontrolled Keywords: neurology,cellular and molecular neuroscience ,/dk/atira/pure/subjectarea/asjc/2800/2808
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
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Depositing User: LivePure Connector
Date Deposited: 16 Jul 2022 00:26
Last Modified: 23 Oct 2022 03:56
URI: https://ueaeprints.uea.ac.uk/id/eprint/86271
DOI: 10.1007/s12035-012-8364-8

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