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Padmanabhan Nair, V. ; Liu, H.* ; Ciceri, G.* ; Jungverdorben, J.* ; Frishman, G. ; Tchieu, J.* ; Cederquist, G.Y.* ; Rothenaigner, I. ; Schorpp, K.K. ; Klepper, L. ; Walsh, R.M.* ; Kim, T.W.* ; Cornacchia, D.* ; Ruepp, A. ; Mayer, J.* ; Hadian, K. ; Frishman, D.* ; Studer, L.* ; Vincendeau, M.

Activation of HERV-K(HML-2) disrupts cortical patterning and neuronal differentiation by increasing NTRK3.

Cell Stem Cell, DOI: 10.1016/j.stem.2021.04.009 (2021)
DOI Order publishers version
: Publ. Version/Full Text online available 05/2022
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-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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Crispr ; Herv ; Ntrk3 ; Neurotrophic Tyrosine Receptor Kinase 3 ; Endogenous Retrovirus ; Forebrain Orgnoid ; Influencing Cortical Neuronal Development ; Retrotransposon
ISSN (print) / ISBN 1934-5909
e-ISSN 1875-9777
Journal Cell Stem Cell
Publisher Cell Press
Publishing Place Cambridge, Mass.
Reviewing status Peer reviewed