The zinc finger/RING domain protein Unkempt regulates cognitive flexibility.
The zinc finger/RING domain protein Unkempt regulates cognitive flexibility.
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DOI：
10.1038/s41598-021-95286-y
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发表时间：
2021-08-11
影响因子：
4.6
通讯作者：
Bateman JM
中科院分区：
文献类型：
--
作者：
Vinsland E;Baskaran P;Mihaylov SR;Hobbs C;Wood H;Bouybayoune I;Shah K;Houart C;Tee AR;Murn J;Fernandes C;Bateman JM
神经系统发育的正确安排是一个深刻的挑战，涉及复杂的分子和细胞过程的协调。雷帕霉素（mTOR）信号传导的机制靶点是神经系统发育和突触功能的关键调节因子。mTOR激酶是感知输入的枢纽，包括生长因子信号，营养物质和能量水平。mTOR信号的激活可引起具有严重神经系统症状的疾病，如结节性硬化症和局灶性皮质发育不良。然而，mTOR信号调节神经系统发育和功能的分子机制尚不清楚。Unkempt是一种保守的锌指/环结构域蛋白，在果蝇中调控mTOR信号下游的神经发生。Unkempt也直接与mTOR复合体I组分Raptor相互作用。在这里，我们描述了在神经系统中有条件敲除Unkempt （UnkcKO）的小鼠的产生和特征。Unkempt缺失会降低胚胎神经系统中Raptor蛋白水平，但不会影响下游mTORC1靶点。我们还发现，unckko小鼠的神经系统发育正常。然而，我们发现Unkempt在成年小脑和海马中表达，行为分析表明UnkcKO小鼠具有改善的记忆形成和重新学习的认知灵活性。进一步了解Unkempt在神经系统中的作用将为mTOR信号在学习和记忆中的作用提供新的机制见解。
Correct orchestration of nervous system development is a profound challenge that involves coordination of complex molecular and cellular processes. Mechanistic target of rapamycin (mTOR) signaling is a key regulator of nervous system development and synaptic function. The mTOR kinase is a hub for sensing inputs including growth factor signaling, nutrients and energy levels. Activation of mTOR signaling causes diseases with severe neurological manifestations, such as tuberous sclerosis complex and focal cortical dysplasia. However, the molecular mechanisms by which mTOR signaling regulates nervous system development and function are poorly understood. Unkempt is a conserved zinc finger/RING domain protein that regulates neurogenesis downstream of mTOR signaling in Drosophila. Unkempt also directly interacts with the mTOR complex I component Raptor. Here we describe the generation and characterisation of mice with a conditional knockout of Unkempt (UnkcKO) in the nervous system. Loss of Unkempt reduces Raptor protein levels in the embryonic nervous system but does not affect downstream mTORC1 targets. We also show that nervous system development occurs normally in UnkcKO mice. However, we find that Unkempt is expressed in the adult cerebellum and hippocampus and behavioural analyses show that UnkcKO mice have improved memory formation and cognitive flexibility to re-learn. Further understanding of the role of Unkempt in the nervous system will provide novel mechanistic insight into the role of mTOR signaling in learning and memory.
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影响因子：
5.3
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通讯作者：
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