Intrauterine growth restriction followed by oxygen support uniquely interferes with genetic regulators of myelination

Jill Chang*, Abhineet Sharma, Mirrah Bashir, Camille M. Fung, Robert W. Dettman, Maria L.V. Dizon

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Intrauterine growth restriction (IUGR) and oxygen exposure in isolation and combination adversely affect the developing brain, putting infants at risk for neurodevelopmental disability including cerebral palsy (CP). Rodent models of IUGR and postnatal hyperoxia have demonstrated oligodendroglial (OL) injury with subsequent white matter injury (WMI) and motor dysfunction. Here, we investigate transcriptomic dysregulation in IUGR with and without hyperoxia exposure to account for the abnormal brain structure and function previously documented. We performed RNA sequencing and analysis using a mouse model of IUGR and found that IUGR, hyperoxia, and the combination of IUGR with hyperoxia (IUGR/hyperoxia) produced distinct changes in gene expression. IUGR in isolation demonstrated the fewest differentially expressed genes (DEGs) compared with control. In contrast, we detected several gene alterations in IUGR/hyperoxia; genes involved in myelination were strikingly downregulated. We also identified changes to specific regulators including TCF7L2, BDNF, SOX2, and DGCR8, through ingenuity pathway analysis (IPA), that may contribute to impaired myelination in IUGR/hyperoxia. Our findings show that IUGR with hyperoxia induces unique transcriptional changes in the developing brain. These indicate mechanisms for increased risk for WMI in IUGR infants exposed to oxygen and suggest potential therapeutic targets to improve motor outcomes.

Original languageEnglish (US)
Article numberENEURO.0263-20.2021
JournaleNeuro
Volume8
Issue number4
DOIs
StatePublished - 2021

Keywords

  • Cerebral palsy
  • Oligodendroglial
  • Perinatal brain injury
  • RNA sequencing
  • White matter injury

ASJC Scopus subject areas

  • Neuroscience(all)

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