Intrauterine growth restriction compromises cerebellar development by affecting radial migration of granule cells via the JamC/Pard3a molecular pathway.
Intrauterine growth restriction compromises cerebellar development by affecting radial migration of granule cells via the JamC/Pard3a molecular pathway.
复制标题
宫内生长受限通过 JamC/Pard3a 分子途径影响颗粒细胞的径向迁移，从而损害小脑发育。
DOI：
10.1016/j.expneurol.2020.113537
复制
发表时间：
2021-03
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;Fattakhov N;Buddington RK;Chizhikov VV
宫内生长受限（IUGR）影响约10%的人类妊娠，导致出生时小于胎龄（SGA）的婴儿，并与运动和认知缺陷有关。人类研究表明，SGA患者的一些缺陷起源于小脑，小脑是一个主要的运动协调和认知中心，但潜在的机制尚不清楚。为了确定IUGR对小脑发育的影响，我们分析了猪作为翻译动物模型，其中一些胎儿由于早发性慢性胎盘功能不全而自发发生IUGR。与人类相似，SGA猪的小脑较小，其内部颗粒细胞层（IGL）中含有较少的成熟颗粒细胞（gc）。令人惊讶的是，新生SGA猪外颗粒层（EGL）中GC前体的增殖增加，这与浦肯野细胞密度增加有关，浦肯野细胞密度增加，已知浦肯野细胞非自主地促进GC的增殖。然而，SGA猪的GCs不能正常启动EGL向IGL的退出，这与引导Bergmann胶质纤维密度降低、促迁移基因Pard3a、JamC和Sema6a表达减少以及细胞凋亡增加有关。虽然在出生后的发育过程中增殖自发正常化，但迁移前GCs的积累和EGL的凋亡是IUGR的长期后果。通过器官型小脑片培养，我们发现，在GCs中以相同的分子途径运作的Pard3a和JamC的正常化表达足以挽救IUGR的迁移性和稍后时间点的凋亡缺陷。因此，由于Pard3a/JamC径向迁移起始通路的中断，EGL中GCs的出口减少是iugr相关小脑病理的主要机制。
Intrauterine growth restriction (IUGR) affects ~10% of human pregnancies, results in infants born small for gestational age (SGA), and is associated with motor and cognitive deficits. Human studies suggest that some deficits in SGA patients originate in the cerebellum, a major motor-coordination and cognitive center, but the underlying mechanisms remain unknown. To identify the cerebellar developmental program affected by IUGR, we analyzed the pig as a translational animal model in which some fetuses spontaneously develop IUGR due to early-onset chronic placental insufficiency. Similar to humans, SGA pigs revealed small cerebella, which contained fewer mature granule cells (GCs) in the internal granule cell layer (IGL). Surprisingly, newborn SGA pigs had increased proliferation of GC precursors in the external granule layer (EGL), which was associated with an increased density of Purkinje cells, known to non-autonomously promote the proliferation of GCs. However, the GCs of SGA pigs did not properly initiate exit from the EGL to IGL, which was associated with a decreased density of guiding Bergmann glial fibers, reduced expression of pro-migratory genes Pard3a, JamC and Sema6a, and increased apoptosis. While proliferation spontaneously normalized during postnatal development, accumulation of pre-migratory GCs and apoptosis in the EGL were long-lasting consequences of IUGR. Using organotypic cerebellar slice cultures, we showed that normalizing expression of Pard3a and JamC, which operate in the same molecular pathway in GCs, was sufficient to rescue both migratory and, at a later time point, apoptotic defects of IUGR. Thus, a decreased exit of GCs from the EGL, due to disrupted Pard3a/JamC radial migration initiation pathway, is a major mechanism of IUGR-related cerebellar pathology.
登录
查看更多内容
影响因子：
4.6
作者：
Blank, Marissa C.;Grinberg, Inessa;Millen, Kathleen J.
通讯作者：
Millen, Kathleen J.
影响因子：
16.6
作者：
Chizhikov, Victor V.;Iskusnykh, Igor Y.;Millen, Kathleen J.
通讯作者：
Millen, Kathleen J.
影响因子：
56.9
作者：
Famulski, Jakub K.;Trivedi, Niraj;Solecki, David J.
通讯作者：
Solecki, David J.
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