Activation of HERV-K(HML-2) Disrupts Cortical Patterning and Neuronal Differentiation by Increasing NTRK3

Overview

Journal Cell Stem Cell

Publisher Cell Press

Specialty Cell Biology

Date 2021 May 5

PMID 33951478

Citations 22

Authors

Vidya Padmanabhan Nair

Hengyuan Liu

Gabriele Ciceri

Johannes Jungverdorben

Goar Frishman

Jason Tchieu

Gustav Y Cederquist

Ina Rothenaigner

Kenji Schorpp

Lena Klepper

Ryan M Walsh

Tae Wan Kim

Daniela Cornacchia

Andreas Ruepp

Jens Mayer

Kamyar Hadian

Dmitrij Frishman

Lorenz Studer

Michelle Vincendeau

Affiliations

Soon will be listed here.

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-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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