Activation of HERV-K(HML-2) disrupts cortical patterning and neuronal differentiation by increasing NTRK3.
Activation of HERV-K(HML-2) disrupts cortical patterning and neuronal differentiation by increasing NTRK3.
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DOI：
10.1016/j.stem.2021.04.009
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发表时间：
2021-09-02
期刊：
影响因子：
23.9
通讯作者：
Vincendeau M
中科院分区：
文献类型：
--
作者：
Padmanabhan Nair V;Liu H;Ciceri G;Jungverdorben J;Frishman G;Tchieu J;Cederquist GY;Rothenaigner I;Schorpp K;Klepper L;Walsh RM;Kim TW;Cornacchia D;Ruepp A;Mayer J;Hadian K;Frishman D;Studer L;Vincendeau M
人类内源性逆转录病毒（HERV）元件的生物学功能和疾病相关性在很大程度上是难以捉摸的。HERV-K（HML-2）与神经毒性有关，但对其作用或机制基础尚无明确认识。我们通过使用CRISPR工程来激活或抑制其在基于人类多能干细胞的系统中的表达水平，解决了HERV-K（HML-2）在神经元分化中的生理功能。我们发现HERV-K（HML-2）转录的升高对皮层神经元的发育和功能是有害的。这些效应是细胞类型特异性的，因为多巴胺能神经元不受影响。此外，高HERV-K（HML-2）转录改变了前脑类器官中的皮质层形成。HERV-K（HML-2）转录激活导致NTRK 3表达和其他神经变性相关基因的过度激活。NTRK 3的直接激活在表型上类似于HERV-K（HML-2）诱导，并且在HERV-K（HML-2）诱导的背景下降低NTRK 3水平恢复皮质神经元分化。因此，这些发现揭示了HERV-K（HML-2）在皮质神经元发育中的细胞类型特异性作用。Vincendeau及其同事证明，内源性逆转录病毒家族HERV-K（HML-2）的激活通过激活经典发育因子NTRK 3对皮质神经元发育产生负面影响。有趣的是，虽然HERV-K（HML-2）活化损害NTRK 3依赖性皮质神经发生，但不依赖于NTRK 3的多巴胺能神经元分化不受影响。
The biological function and disease association of human endogenous retroviral (HERV) elements is largely elusive. HERV-K(HML-2) has been associated with neurotoxicity but there is no clear understanding of its role or mechanistic basis. We addressed the physiological functions of HERV-K(HML-2) in neuronal differentiation by using CRISPR engineering to activate or repress its expression levels in a human pluripotent stem cell-based system. We found that elevated HERV-K(HML-2) transcription is detrimental for the development and function of cortical neurons. These effects are cell type-specific, as dopaminergic neurons are unaffected. Moreover, high HERV-K(HML-2) transcription alters cortical layer formation in forebrain organoids. HERV-K(HML-2) transcriptional activation leads to hyperactivation of NTRK3 expression and other neurodegeneration-related genes. Direct activation of NTRK3 phenotypically resembles HERV-K(HML-2) induction, and reducing NTRK3 levels in context of HERV-K(HML-2) induction restores cortical neuron differentiation. Hence, these findings unravel a cell type-specific role for HERV-K(HML-2) in cortical neuron development. Vincendeau and colleagues demonstrate that activation of the endogenous retrovirus family HERV-K(HML-2) negatively impacts cortical neuronal development by activating the classical developmental factor NTRK3. Intriguingly, while HERV-K(HML-2) activation impairs NTRK3 dependent cortical neurogenesis, NTRK3 independent dopaminergic neuronal differentiation is not affected.
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影响因子：
4.7
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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通讯作者：
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通讯作者：
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