CASK loss of function differentially regulates neuronal maturation and synaptic function in human induced cortical excitatory neurons.
CASK loss of function differentially regulates neuronal maturation and synaptic function in human induced cortical excitatory neurons.
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DOI：
10.1016/j.isci.2022.105187
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发表时间：
2022-10-21
期刊：
影响因子：
5.8
通讯作者：
Pak, ChangHui
中科院分区：
文献类型：
--
作者：
McSweeney, Danny;Gabriel, Rafael;Jin, Kang;Pang, Zhiping P.;Aronow, Bruce;Pak, ChangHui
CASK中的功能丧失（LOF）突变导致严重的发育表型，包括伴有脑桥和小脑发育不全的小头畸形、X连锁智力残疾和自闭症。由于有限的人类细胞模型来研究这种分子在神经元成熟和突触发育过程中的动态作用，解开CASK相关疾病的病理机制一直具有挑战性。在这里，我们研究细胞自主功能的CASK在皮质兴奋性诱导神经元（iNs）产生的CASK敲除（KO）的同基因人胚胎干细胞（hESC）使用基因表达，形态计量学和电生理学。虽然未成熟的CASK KO iN显示出稳健的神经元生长，但成熟的CASK KO iN显示出突触传递和同步网络活动的严重缺陷，而不损害神经元形态和突触数量。在发育中的人类皮层兴奋性神经元中，CASK的功能是促进结构完整性和皮层兴奋性神经元网络的建立。这些结果奠定了基础，为未来的研究，确定这些表型相关的人类患者的抑制剂。CASK缺乏的人诱导兴奋性神经元模型CASK LOF突变增加发育中兴奋性神经元的神经元复杂性CASK LOF导致成熟兴奋性神经元的突触损伤CASK突变调节遗传背景中的核心基因组自然科学;生物科学;神经科学;分子神经科学;细胞神经科学
Loss-of-function (LOF) mutations in CASK cause severe developmental phenotypes, including microcephaly with pontine and cerebellar hypoplasia, X-linked intellectual disability, and autism. Unraveling the pathological mechanisms of CASK-related disorders has been challenging owing to limited human cellular models to study the dynamic roles of this molecule during neuronal maturation and synapse development. Here, we investigate cell-autonomous functions of CASK in cortical excitatory induced neurons (iNs) generated from CASK knockout (KO) isogenic human embryonic stem cells (hESCs) using gene expression, morphometrics, and electrophysiology. While immature CASK KO iNs show robust neuronal outgrowth, mature CASK KO iNs display severe defects in synaptic transmission and synchronized network activity without compromising neuronal morphology and synapse numbers. In the developing human cortical excitatory neurons, CASK functions to promote both structural integrity and establishment of cortical excitatory neuronal networks. These results lay the foundation for future studies identifying suppressors of such phenotypes relevant to human patients. Human-induced excitatory neuronal model of CASK deficiency CASK LOF mutations increase neuronal complexity in developing excitatory neurons CASK LOF causes synaptic impairment in mature excitatory neurons CASK mutations regulate a core set of genes across genetic backgrounds Natural sciences; Biological sciences; Neuroscience; Molecular neuroscience; Cellular neuroscience
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DOI：
10.1083/jcb.200712094
发表时间：
2008-07-14
期刊：
The Journal of cell biology
影响因子：
--
作者：
Chao HW;Hong CJ;Huang TN;Lin YL;Hsueh YP
通讯作者：
Hsueh YP
影响因子：
3.5
作者：
Chen, Kaiyun;Featherstone, David E.
通讯作者：
Featherstone, David E.
影响因子：
16.2
作者：
Kawabe, Hiroshi;Neeb, Antje;Dimova, Kalina;Young, Samuel M., Jr.;Takeda, Michiko;Katsurabayashi, Shutaro;Mitkovski, Miso;Malakhova, Oxana A.;Zhang, Dong-Er;Ulmilkawa, Masato;Kariya, Ken-ichi;Goebbels, Sandra;Nave, Klaus-Armin;Rosenmund, Christian;Jahn, Olaf;Rhee, JeongSeop;Brose, Nils
通讯作者：
Brose, Nils
影响因子：
14.9
作者：
Chen J;Bardes EE;Aronow BJ;Jegga AG
通讯作者：
Jegga AG
影响因子：
11.2
作者：
Hsueh, Yi-Ping
通讯作者：
Hsueh, Yi-Ping