Loss-of-Function of p21-Activated Kinase 2 Links BMP Signaling to Neural Tube Patterning Defects.
Loss-of-Function of p21-Activated Kinase 2 Links BMP Signaling to Neural Tube Patterning Defects.
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p21 功能丧失 - 激活激酶 2 将 BMP 信号转导与神经管图案缺陷联系起来
DOI：
10.1002/advs.202204018
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发表时间：
2023-03
期刊：
影响因子：
15.1
通讯作者：
Sun, Zhong Sheng
中科院分区：
文献类型：
--
作者：
Wang, Yan;Zhang, Kaifan;Guo, Jin;Yang, Shuyan;Shi, Xiaohui;Pan, Jinrong;Sun, Zheng;Zou, Jizhen;Li, Yi;Li, Yuanyuan;Fan, Tianda;Song, Wei;Cheng, Fang;Zeng, Cheng;Li, Jinchen;Zhang, Ting;Sun, Zhong Sheng
神经管的闭合是一个高度复杂和协调的过程，其失败构成常见的出生缺陷。丝氨酸/苏氨酸激酶p21激活激酶2（PAK 2）是细胞骨架动力学的关键调节因子;然而，其在神经形成和神经管缺陷（NTD）发病机制中的作用仍不清楚。在这里，结果表明Pak 2 −/−小鼠胚胎未能发育背外侧铰链点（DLHP），并表现出颅脊柱裂，这是一种严重的NTD表型。Pak 2基因敲除激活了参与脊椎动物骨形成的BMP信号传导。单细胞转录组揭示了Pak 2 −/−小鼠胚胎在神经管发育过程中的异常分化轨迹和转录事件。在5个人NTD胎儿中鉴定了PAK 2基因中的两个非同义突变和一个复发性剪接位点突变，这些胎儿在脑中表现出PAK 2表达减弱和BMP信号上调。在机制上，PAK 2调节Smad 9磷酸化以抑制BMP信号传导并最终诱导DLHP形成。斑马鱼中pak 2a的缺失诱导神经管缺陷，这些缺陷部分被野生型而不是突变型PAK 2的过表达所挽救。这些发现表明PAK 2在多种脊椎动物神经形成中的保守作用，突出了NTD中PAK 2突变的分子发病机制。p21活化激酶2（PAK 2）通过调节Smad 9磷酸化抑制骨形态发生蛋白（BMP）信号传导诱导背外侧铰链点（DLHP）。Pak 2 −/−小鼠和pak 2a Δ14斑马鱼无法关闭神经管。携带PAK 2突变的人类神经管缺陷（NTD）表现出异常的PAK 2表达和BMP信号传导。Pak 2基因敲除诱导神经管发育过程中的异常分化轨迹。
Closure of the neural tube represents a highly complex and coordinated process, the failure of which constitutes common birth defects. The serine/threonine kinase p21‐activated kinase 2 (PAK2) is a critical regulator of cytoskeleton dynamics; however, its role in the neurulation and pathogenesis of neural tube defects (NTDs) remains unclear. Here, the results show that Pak2 −/− mouse embryos fail to develop dorsolateral hinge points (DLHPs) and exhibit craniorachischisis, a severe phenotype of NTDs. Pak2 knockout activates BMP signaling that involves in vertebrate bone formation. Single‐cell transcriptomes reveal abnormal differentiation trajectories and transcriptional events in Pak2 −/− mouse embryos during neural tube development. Two nonsynonymous and one recurrent splice‐site mutations in the PAK2 gene are identified in five human NTD fetuses, which exhibit attenuated PAK2 expression and upregulated BMP signaling in the brain. Mechanistically, PAK2 regulates Smad9 phosphorylation to inhibit BMP signaling and ultimately induce DLHP formation. Depletion of pak2a in zebrafish induces defects in the neural tube, which are partially rescued by the overexpression of wild‐type, but not mutant PAK2. The findings demonstrate the conserved role of PAK2 in neurulation in multiple vertebrate species, highlighting the molecular pathogenesis of PAK2 mutations in NTDs. p21‐activated kinase 2 (PAK2) inhibits bone morphogenic protein (BMP) signaling to induce dorsolateral hinge point (DLHP) through regulation of Smad9 phosphorylation. Pak2 −/− mouse and pak2a Δ14 zebrafish fail to close the neural tube. Human neural tube defects (NTDs) carrying PAK2 mutations exhibit abnormal PAK2 expression and BMP signaling. Pak2 knockout induces abnormal differentiation trajectories during neural tube development.
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影响因子：
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发表时间：
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影响因子：
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作者：
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