Activation of HERV-K(HML-2) disrupts cortical patterning and neuronal differentiation by increasing NTRK3 Journal Article
| Authors: | Nair, V. P.; Liu, H. Y.; Ciceri, G.; Jungverdorben, J.; Frishman, G.; Tchieu, J.; Cederquist, G. Y.; Rothenaigner, I.; Schorpp, K.; Klepper, L.; Walsh, R. M.; Kim, T. W.; Cornacchia, D.; Ruepp, A.; Mayer, J.; Hadian, K.; Frishman, D.; Studer, L.; Vincendeau, M. |
| Article Title: | Activation of HERV-K(HML-2) disrupts cortical patterning and neuronal differentiation by increasing NTRK3 |
| Abstract: | The biological function and disease association of human endogenous retroviruses (HERVs) are 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 using CRISPR engineering to activate or repress its expression levels in a human-pluripotent-stemcell-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. |
| Keywords: | human genome; gene-expression; cells; transcriptional activity; human es; transposable elements; dopamine neurons; herv-k; comprehensive analysis; human endogenous retroviruses |
| Journal Title: | Cell Stem Cell |
| Volume: | 28 |
| Issue: | 9 |
| ISSN: | 1934-5909 |
| Publisher: | Cell Press |
| Date Published: | 2021-09-02 |
| Start Page: | 1566 |
| End Page: | 1581 |
| Language: | English |
| ACCESSION: | WOS:000692518000008 |
| DOI: | 10.1016/j.stem.2021.04.009 |
| PROVIDER: | wos |
| PMCID: | PMC8419085 |
| PUBMED: | 33951478 |
| Notes: | Article -- Source: Wos |
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