Impaired Function of PLEKHG2, a Rho-Guanine Nucleotide-Exchange Factor, Disrupts Corticogenesis in Neurodevelopmental Phenotypes.
Impaired Function of PLEKHG2, a Rho-Guanine Nucleotide-Exchange Factor, Disrupts Corticogenesis in Neurodevelopmental Phenotypes.
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Rho-Guanine核苷酸交换因子Plekhg2的功能受损，破坏了神经发育表型中的皮质生成。
DOI：
10.3390/cells11040696
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发表时间：
2022-02-16
期刊：
影响因子：
6
通讯作者：
Nagata KI
中科院分区：
文献类型：
--
作者：
Nishikawa M;Ito H;Tabata H;Ueda H;Nagata KI
PLEKHG 2基因编码Rho家族特异性鸟嘌呤核苷酸交换因子，其PLEKHG 2基因中P.Arg204Trp变异的纯合性与智力残疾的小头畸形有关。然而，PLEKHG 2在神经发育过程中的作用仍然未知。在这项研究中，我们分析了小鼠Plekhg 2功能在皮质发育过程中，在体外和体内。小鼠中的p.Arg200Trp变体（Plekhg 2-RW）对应于人类中的p.Arg204Trp变体，显示Rac 1、Rac 3和Cdc 42的鸟嘌呤核苷酸交换活性降低。使用子宫内电穿孔介导的基因转移急性敲除Plekhg 2并不影响皮质生成过程中兴奋性神经元的迁移。另一方面，沉默Plekhg 2表达延迟出生后第7天（P7）的树突状乔木形成，可能是因为受损的Rac/Cdc 42和p21激活的激酶1信号通路。这种表型通过表达野生型Plekhg 2的RNAi抗性版本而不是Plekhg 2-RW来拯救。轴突寻路也受损，在体外和体内Plekhg 2缺陷的皮层神经元。在P14，观察到Plekhg 2的敲低导致树突棘形态形成缺陷。总的来说，这些结果强烈表明，PLEKHG 2在轴突，树突和棘的成熟中具有重要作用。此外，PLEKHG 2功能的损伤最有可能引起神经元功能的缺陷，从而导致神经发育障碍。
Homozygosity of the p.Arg204Trp variation in the Pleckstrin homology and RhoGEF domain containing G2 (PLEKHG2) gene, which encodes a Rho family-specific guanine nucleotide-exchange factor, is responsible for microcephaly with intellectual disability. However, the role of PLEKHG2 during neurodevelopment remains unknown. In this study, we analyzed mouse Plekhg2 function during cortical development, both in vitro and in vivo. The p.Arg200Trp variant in mouse (Plekhg2-RW), which corresponds to the p.Arg204Trp variant in humans, showed decreased guanine nucleotide-exchange activity for Rac1, Rac3, and Cdc42. Acute knockdown of Plekhg2 using in utero electroporation-mediated gene transfer did not affect the migration of excitatory neurons during corticogenesis. On the other hand, silencing Plekhg2 expression delayed dendritic arbor formation at postnatal day 7 (P7), perhaps because of impaired Rac/Cdc42 and p21-activated kinase 1 signaling pathways. This phenotype was rescued by expressing an RNAi-resistant version of wildtype Plekhg2, but not of Plekhg2-RW. Axon pathfinding was also impaired in vitro and in vivo in Plekhg2-deficient cortical neurons. At P14, knockdown of Plekhg2 was observed to cause defects in dendritic spine morphology formation. Collectively, these results strongly suggest that PLEKHG2 has essential roles in the maturation of axon, dendrites, and spines. Moreover, impairment of PLEKHG2 function is most likely to cause defects in neuronal functions that lead to neurodevelopmental disorders.
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影响因子：
3.4
作者：
Da Silva JD;Costa MD;Almeida B;Lopes F;Maciel P;Teixeira-Castro A
通讯作者：
Teixeira-Castro A
影响因子：
2.2
作者：
Edvardson, Simon;Wang, Haibo;Elpeleg, Orly
通讯作者：
Elpeleg, Orly
影响因子：
6
作者：
Scala M;Nishikawa M;Nagata KI;Striano P
通讯作者：
Striano P
影响因子：
5.3
作者：
Friocourt, Gaeelle;Kanatani, Shigeaki;Parnavelas, John G.
通讯作者：
Parnavelas, John G.
影响因子：
16.2
作者：
Dimidschstein, Jordane;Passante, Lara;Vanderhaeghen, Pierre
通讯作者：
Vanderhaeghen, Pierre