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Modeling Encephalopathy of Prematurity Using Prenatal Hypoxia-ischemia with Intra-amniotic Lipopolysaccharide in Rats
Published on: November 20, 2015
Region specific oligodendrocyte transcription factor expression in a model of neonatal hypoxic injury
Bethann M Affeldt1, Andre Obenaus2, Jonathan Chan1
1Department of Pediatrics, Loma Linda University, 11175 Campus St., Coleman Pavilion Room A1109, Loma Linda, CA, 92354, USA.
Insights
Hypoxia in preterm infants impairs oligodendrocyte development, leading to white matter injury (WMI). This study identifies key transcription factors (Ascl1, Olig1, Nkx2.2) that, when altered, cause delayed myelination and suggest potential therapeutic targets for WMI.
Area of Science:
- Neuroscience
- Developmental Biology
- Pathology
Background:
- White matter injury (WMI) in preterm infants is linked to neurological deficits.
- Impaired oligodendrocyte development post-hypoxia is a suspected cause of WMI.
- Mechanisms underlying hypoxia-induced WMI remain unclear.
Purpose of the Study:
- To investigate alterations in oligodendrocyte precursor cell transcription factors following transient mild global hypoxia.
- To identify molecular targets for treating WMI in premature infants.
Main Methods:
- Postnatal day 7 mice exposed to 60 minutes of hypoxia (7.5% O2).
- Analysis of oligodendrocyte differentiation markers (Ascl1, Olig1, Olig2, Nkx2.2, APC) and myelin proteins (MAG, MBP) at P9, P14, and P28.
- Comparison of gene expression and myelination in white matter tracts between hypoxic and sham groups.
Main Results:
- Transient hypoxia altered expression of Ascl1, Olig1, and Nkx2.2.
- Delayed myelination was observed in the external capsule.
- Oligodendrocyte progenitor cells specified before hypoxia were more vulnerable to maturation arrest.
Conclusions:
- Altered Ascl1, Olig1, and Nkx2.2 expression contributes to impaired oligodendrocyte differentiation and myelination in WMI.
- These transcription factors represent potential therapeutic targets for WMI.
- Timing of oligodendrocyte progenitor cell specification influences susceptibility to hypoxic injury.
Abstract:
White matter injury (WMI) of prematurity is associated with a spectrum of neurological disorders ranging from mild cognitive and behavioral deficits to cerebral palsy. Translational studies have implicated impaired oligodendrocyte development after hypoxia as the primary cause of WMI, but the underlying mechanisms remain poorly understood. The goal of this study was to identify alterations in the expression of oligodendrocyte precursor cell transcription factors in a mouse model of transient mild global hypoxia. Postnatal day (P) 7 mouse pups were exposed to hypoxia (7.5% O2) for 60minutes. We compared oligodendrocyte differentiation and subsequent myelin formation between hypoxia and sham animals at P9, P14 and P28 by examining the expression of key transcription factor regulators of oligodendrocyte differentiation (Ascl1, Olig1, Olig2, and Nkx2.2), as well as APC, a mature oligodendrocyte marker, in the major white matter regions including the corpus callosum, external capsule and anterior commissure. We also examined the effect on myelin formation by examining two myelin specific protein constituents, myelin associated glycoprotein (MAG) and myelin basic protein (MBP), in white matter tracts and whole brain lysate respectively. We found that transient hypoxia at P7 altered the expression of Ascl1, Olig1 and Nkx2.2, resulting in delayed myelination in the external capsule. In addition, our study showed that oligodendrocyte progenitor cells specified several days prior to a hypoxic event are more susceptible to maturation arrest than those specified shortly prior to hypoxia. Our results suggest that alterations of Ascl1, Olig1 and Nkx2.2 underlie impaired oligodendrocyte differentiation and deficient myelination in WMI. These transcription factors are potential therapeutic targets for the treatment of WMI in preterm infants.
