Delayed myelination in an intrauterine growth retardation model is mediated by oxidative stress upregulating bone morphogenetic protein 4.
Delayed myelination in an intrauterine growth retardation model is mediated by oxidative stress upregulating bone morphogenetic protein 4.
复制标题
DOI：
10.1097/nen.0b013e31825cfa81
复制
发表时间：
2012-07
影响因子：
3.2
通讯作者：
Grinspan JB
中科院分区：
文献类型：
--
作者：
Reid MV;Murray KA;Marsh ED;Golden JA;Simmons RA;Grinspan JB
宫内生长迟缓（IUGR）与脑瘫、认知和行为障碍等神经功能障碍有关。其发病机制涉及氧化应激，导致心室周围白质损伤，伴成熟少突胶质细胞缺乏和髓鞘化降低。这种损伤背后的分子机制仍然知之甚少。我们采用胚胎第19天通过双侧子宫动脉结扎造成的IUGR大鼠模型，导致胎儿生长迟缓和发育中的大脑氧化应激。IUGR大鼠幼崽在少突胶质细胞分化和髓鞘形成方面表现出明显的延迟，这种延迟在8周后消退。抑制少突胶质细胞成熟的骨形态发生蛋白4 （Bone morphogenetic protein 4, BMP4）在IUGR大脑中在出生后的时间点升高，到成年时恢复到接近正常水平。尽管有明显的恢复，但在8周大的雌性动物中发现了行为缺陷，这表明早期短暂的髓鞘发育缺陷具有永久性影响。为了支持这些体内数据，从出生后IUGR大鼠培养的少突胶质前体细胞保留了增加的BMP4表达和分化受损，这与BMP抑制剂noggin逆转。少突胶质细胞中的氧化剂增加BMP表达，减少分化；然而，在体外和BMP缺陷小鼠中，用noggin去除BMP信号传导可以阻止这些作用。综上所述，这些发现表明IUGR通过产生氧化应激导致BMP4上调而导致髓鞘形成延迟。
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 employed 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.