Delayed myelination in an intrauterine growth retardation model is mediated by oxidative stress upregulating bone morphogenetic protein 4.
Intrauterine growth retardation (IUGR) is associated with neurological deficits including cerebral palsy and cognitive and behavioral disabilities. The pathogenesis involves oxidative stress that leads to periventricular white matter injury with a paucity of mature oligodendrocytes and hypomyelination. The molecular mechanisms underlying this damage remain poorly understood. We used a rat model of IUGR created by bilateral ligation of the uterine artery at embryonic Day 19 that results in fetal growth retardation and oxidative stress in the developing brain. The IUGR rat pups showed significant delays in oligodendrocyte differentiation and myelination that resolved by 8 weeks. Bone morphogenetic protein 4 (BMP4), which inhibits oligodendrocyte maturation, was elevated in IUGR brains at postnatal time points and returned to near normal by adulthood. Despite the apparent recovery, behavioral deficiencies were found in 8-week-old female animals, suggesting that the early transient myelination defects have permanent effects. In support of these in vivo data, oligodendrocyte precursor cells cultured from postnatal IUGR rats retained increased BMP4 expression and impaired differentiation that was reversed with the BMP inhibitor noggin. Oxidants in oligodendrocyte cultures increased BMP expression, which decreased differentiation; however, abrogating BMP signaling with noggin in vitro and in BMP-deficient mice prevented these effects. Together, these findings suggest that IUGR results in delayed myelination through the generation of oxidative stress that leads to BMP4 upregulation.
Department of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
Mary V
MV
Reid
Kaitlin A
KA
Murray
Eric D
ED
Marsh
Jeffrey A
JA
Golden
Rebecca A
RA
Simmons
Judith B
JB
Grinspan
D000447:Aldehydes / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism*; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000172:deficiency; D001921:Brain / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D005317:Fetal Growth Retardation / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D018507:Gene Expression Regulation, Developmental; D018737:Hand Strength / Q000502:physiology; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000235:genetics / Q000473:pathology; D020932:Nerve Growth Factor / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology*; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000502:physiology*
D000447:Aldehydes; D055415:Bone Morphogenetic Protein 4; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D020932:Nerve Growth Factor; D052005:Bone Morphogenetic Protein Receptors, Type I; C027576:4-hydroxy-2-nonenal