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doi:10.22028/D291-42633
Title: | Activation of HERV-K(HML-2) disrupts cortical patterning and neuronal differentiation by increasing NTRK3 |
Author(s): | Padmanabhan Nair, Vidya Liu, Hengyuan Ciceri, Gabriele Jungverdorben, Johannes Frishman, Goar Tchieu, Jason Cederquist, Gustav Y. Rothenaigner, Ina Schorpp, Kenji Klepper, Lena Walsh, Ryan M. Kim, Tae Wan Cornacchia, Daniela Ruepp, Andreas Mayer, Jens Hadian, Kamyar Frishman, Dmitrij Studer, Lorenz Vincendeau, Michelle |
Language: | English |
Title: | Cell Stem Cell |
Volume: | 28 |
Issue: | 9 |
Pages: | 1566-1581 |
Publisher/Platform: | Cell Press |
Year of Publication: | 2021 |
Free key words: | HERV endogenous retrovirus retrotransposon CRISPR influencing cortical neuronal development Neurotrophic Tyrosine Receptor Kinase 3 NTRK3 forebrain orgnoid |
DDC notations: | 610 Medicine and health |
Publikation type: | Journal Article |
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. |
DOI of the first publication: | 10.1016/j.stem.2021.04.009 |
URL of the first publication: | https://doi.org/10.1016/j.stem.2021.04.009 |
Link to this record: | urn:nbn:de:bsz:291--ds-426331 hdl:20.500.11880/38236 http://dx.doi.org/10.22028/D291-42633 |
ISSN: | 1934-5909 |
Date of registration: | 12-Aug-2024 |
Description of the related object: | Supplemental information |
Related object: | https://ars.els-cdn.com/content/image/1-s2.0-S1934590921001661-mmc1.pdf https://ars.els-cdn.com/content/image/1-s2.0-S1934590921001661-mmc2.pdf |
Faculty: | M - Medizinische Fakultät |
Department: | M - Humangenetik |
Professorship: | M - Prof. Dr. Eckart Meese |
Collections: | SciDok - Der Wissenschaftsserver der Universität des Saarlandes |
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