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Intrauterine Growth Restriction Followed by Oxygen Support Uniquely Interferes with Genetic Regulators of Myelination

Jill Chang1, Robert H Lurie2, Abhineet Sharma2

  • 1Department of Pediatrics, Division of Neonatology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611 jill.chang@northwestern.edu.

Eneuro
|June 8, 2021
PubMed

Insights

Intrauterine growth restriction (IUGR) and postnatal hyperoxia uniquely alter brain gene expression, particularly downregulating myelination genes. This combination increases the risk of white matter injury and motor deficits in infants.

Area of Science:

  • Neuroscience
  • Developmental Biology
  • Genomics

Background:

  • Intrauterine growth restriction (IUGR) and postnatal hyperoxia are known risk factors for infant neurodevelopmental disabilities.
  • These conditions can lead to white matter injury (WMI) and motor dysfunction, particularly in developing brains.
  • Previous studies in rodent models showed oligodendroglial injury and WMI.

Purpose of the Study:

  • To investigate the transcriptomic dysregulation in the developing brain caused by IUGR and/or hyperoxia exposure.
  • To identify specific gene expression changes and regulatory pathways affected by these perinatal insults.
  • To understand the molecular mechanisms underlying WMI and motor deficits in IUGR infants exposed to oxygen.

Main Methods:

  • Utilized a mouse model of IUGR.
  • Performed RNA sequencing and analysis on brain tissue from control, IUGR, hyperoxia, and IUGR/hyperoxia groups.
  • Applied Ingenuity Pathway Analysis to identify key regulatory genes.

Main Results:

  • IUGR alone showed minimal gene expression changes compared to controls.
  • The combination of IUGR and hyperoxia (IUGR/hyperoxia) resulted in significant gene alterations.
  • Genes crucial for myelination (development, maintenance, and remyelination) were notably downregulated in the IUGR/hyperoxia group.
  • Key regulators like TCF7L2, BDNF, SOX2, and DGCR8 were identified as potentially contributing to impaired myelination.

Conclusions:

  • Combined IUGR and hyperoxia exposure induces unique transcriptional changes in the developing brain.
  • These findings suggest specific molecular mechanisms contributing to increased WMI risk in IUGR infants exposed to oxygen.
  • Understanding these gene perturbations highlights potential therapeutic targets for improving motor outcomes and emphasizes the need for controlled oxygen use.

Keywords:
RNA sequencingcerebral palsyoligodendroglialperinatal brain injurywhite matter injury

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