Preterm birth disrupts cerebellar development by affecting granule cell proliferation program and Bergmann glia.
Preterm birth disrupts cerebellar development by affecting granule cell proliferation program and Bergmann glia.
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DOI：
10.1016/j.expneurol.2018.05.015
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发表时间：
2018-08
影响因子：
5.3
通讯作者：
Chizhikov VV
中科院分区：
文献类型：
--
作者：
Iskusnykh IY;Buddington RK;Chizhikov VV
早产是导致长期运动和认知障碍的主要原因。临床研究表明，其中一些缺陷是由小脑发育障碍引起的，但导致早产儿小脑异常的机制在很大程度上尚不清楚。此外，尚不清楚早产和早产暴露在宫外环境中是直接破坏小脑发育，还是间接增加小脑损伤的可能性，包括与早产儿护理相关的临床干预和方案造成的损伤。在这项研究中，我们分析了91%足月经剖腹产的早产猪的小脑，并饲养了10天，直到足月等龄。这些猪没有接受任何已知或怀疑会影响小脑发育的治疗，也没有脑损伤的证据。以出生时处死的足月猪为对照。免疫组织化学分析显示，早产对足月同龄的浦肯野细胞或分子层中间神经元的大小和数量都没有影响。然而，早产猪的颗粒细胞前体和Bergmann胶质纤维的数量减少。早产猪颗粒细胞增殖减少，但分化不明显。激光捕获显微切割的外周颗粒细胞层的QRT-PCR分析表明，早产猪细胞周期蛋白D1和B1、颗粒细胞主要调控转录因子Atoh1和信号分子Jag1的表达减少。体外抢救实验证实Jag1是一个受早产影响的中央颗粒细胞基因。因此，早产和早熟暴露于宫外环境中，通过调节小脑关键发育基因的表达，主要影响颗粒前体和Bergmann胶质细胞的发育，从而扰乱小脑。
Preterm birth is a leading cause of long-term motor and cognitive deficits. Clinical studies suggest that some of these deficits result from disruption of cerebellar development, but the mechanisms that mediate cerebellar abnormalities in preterm infants are largely unknown. Furthermore, it remains unclear whether preterm birth and precocious exposure to the ex-utero environment directly disrupt cerebellar development or indirectly by increasing the probability of cerebellar injury, including that resulting from clinical interventions and protocols associated with the care of preterm infants. In this study, we analyzed the cerebellum of preterm pigs delivered via c-section at 91% term and raised for 10 days, until term-equivalent age. The pigs did not receive any treatments known or suspected to affect cerebellar development and had no evidence of brain damage. Term pigs sacrificed at birth were used as controls. Immunohistochemical analysis revealed that preterm birth did not affect either size or numbers of Purkinje cells or molecular layer interneurons at term-equivalent age. The number of granule cell precursors and Bergmann glial fibers, however, were reduced in preterm pigs. Preterm pigs had reduced proliferation but not differentiation of granule cells. qRT-PCR analysis of laser capture microdissected external granule cell layer showed that preterm pigs had a reduced expression of Cyclins D1 and B1, granule cell master regulatory transcription factor Atoh1, and signaling molecule Jag1. In vitro rescue experiments identified Jag1 as a central granule cell gene affected by preterm birth. Thus, preterm birth and precocious exposure to the ex-utero environment disrupt cerebellum by modulating expression of key cerebellar developmental genes, predominantly affecting development of granule precursors and Bergmann glia.
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影响因子：
6.1
作者：
Biran, Valerie;Heine, Vivi M.;Verney, Catherine;Sheldon, R. Ann;Spadafora, Ruggero;Vexler, Zinaida S.;Rowitch, David H.;Ferriero, Donna M.
通讯作者：
Ferriero, Donna M.
影响因子：
17.1
作者：
Baud, Olivier;Gressens, Pierre
通讯作者：
Gressens, Pierre
影响因子：
2.5
作者：
Faust, PL
通讯作者：
Faust, PL
影响因子：
4.6
作者：
Fauquier, Teddy;Chatonnet, Fabrice;Flamant, Frederic
通讯作者：
Flamant, Frederic
DOI：
10.1126/science.1181453
发表时间：
2009-12-04
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Flora A;Klisch TJ;Schuster G;Zoghbi HY
通讯作者：
Zoghbi HY