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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 28, 1566-1581.e8 (2021)
Postprint Forschungsdaten DOI PMC
Open Access Green
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Crispr ; Herv ; Ntrk3 ; Neurotrophic Tyrosine Receptor Kinase 3 ; Endogenous Retrovirus ; Forebrain Orgnoid ; Influencing Cortical Neuronal Development ; Retrotransposon; Human Endogenous Retroviruses; Herv-k; Transcriptional Activity; Comprehensive Analysis; Transposable Elements; Dopamine Neurons; Gene-expression; Human Genome; Human Es; Cells
ISSN (print) / ISBN 1934-5909
e-ISSN 1875-9777
Zeitschrift Cell Stem Cell
Quellenangaben Band: 28, Heft: 9, Seiten: 1566-1581.e8 Artikelnummer: , Supplement: ,
Verlag Cell Press
Verlagsort Cambridge, Mass.
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Virology (VIRO)
Institute of Experimental Genetics (IEG)
Institute of Molecular Toxicology and Pharmacology (TOXI)
Förderungen New York State Stem Cell Science (NYSTEM, USA) postdoctoral fellowship
EMBO long-term postdoctoral fellowship from the European Molecular Biology Organization
National Institute of Health (NIH, USA)
Deutsche Forschungs Gemeinschaft (DFG, Germany)