McDougall Annie R A, Wiradjaja Vanny, Azhan Aminath, Li Anqi, Hale Nadia, Wlodek Mary E, Hooper Stuart B, Wallace Megan J, Tolcos Mary
The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC, Australia.
Dev Neurosci. 2017;39(1-4):215-227. doi: 10.1159/000470902. Epub 2017 Apr 28.
Intrauterine growth restriction (IUGR) is a major cause of antenatal brain injury. We aimed to characterize cerebellar deficits following IUGR and to investigate the potential underlying cellular and molecular mechanisms. At embryonic day 18, pregnant rats underwent either sham surgery (controls; n = 23) or bilateral uterine vessel ligation to restrict blood flow to fetuses (IUGR; n = 20). Offspring were collected at postnatal day 2 (P2), P7, and P35. Body weights were reduced at P2, P7, and P35 in IUGR offspring (p < 0.05) compared with controls. At P7, the width of the external granule layer (EGL) was 30% greater in IUGR than control rats (p < 0.05); there was no difference in the width of the proliferative zone or in the density of Ki67-positive cells in the EGL. Bergmann glia were disorganized at P7 and P35 in IUGR pups, and by P35, there was a 10% decrease in Bergmann glial fiber density (p < 0.05) compared with controls. At P7, trophoblast antigen-2 (Trop2) mRNA and protein levels in the cerebellum were decreased by 88 and 40%, respectively, and astrotactin 1 mRNA levels were increased by 20% in the IUGR rats (p < 0.05) compared with controls; there was no difference in ASTN1 protein. The expressions of other factors known to regulate cerebellar development (astrotactin 2, brain-derived neurotrophic factor, erb-b2 receptor tyrosine kinase 4, neuregulin 1, sonic hedgehog and somatostatin) were not different between IUGR and control rats at P7 or P35. These data suggest that damage to the migratory scaffold (Bergmann glial fibers) and alterations in the genes that influence migration (Trop2 and Astn1) may underlie the deficits in postnatal cerebellar development following IUGR.
宫内生长受限（IUGR）是产前脑损伤的主要原因。我们旨在描述IUGR后的小脑缺陷，并研究其潜在的细胞和分子机制。在胚胎第18天，对怀孕大鼠进行假手术（对照组；n = 23）或双侧子宫血管结扎以限制胎儿的血流（IUGR组；n = 20）。在出生后第2天（P2）、P7和P35收集后代。与对照组相比，IUGR后代在P2、P7和P35时体重降低（p < 0.05）。在P7时，IUGR大鼠的外颗粒层（EGL）宽度比对照大鼠大30%（p < 0.05）；增殖区宽度或EGL中Ki67阳性细胞密度无差异。IUGR幼崽在P7和P35时Bergmann胶质细胞排列紊乱，到P35时，与对照组相比，Bergmann胶质纤维密度降低10%（p < 0.05）。在P7时，IUGR大鼠小脑中滋养层抗原2（Trop2）的mRNA和蛋白水平分别降低88%和40%，astrotactin 1的mRNA水平升高20%（p < 0.05）；ASTN1蛋白无差异。已知调节小脑发育的其他因子（astrotactin 2、脑源性神经营养因子、erb-b2受体酪氨酸激酶4、神经调节蛋白1、音猬因子和生长抑素）在P7或P35时IUGR大鼠和对照大鼠之间无差异。这些数据表明，迁移支架（Bergmann胶质纤维）的损伤以及影响迁移的基因（Trop2和Astn1）的改变可能是IUGR后出生后小脑发育缺陷的基础。
