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

Vidya Padmanabhan Nair1, Hengyuan Liu2, Gabriele Ciceri3

  • 1Institute of Virology, Helmholtz Zentrum München, Neuherberg, Germany.

Cell Stem Cell
|May 5, 2021
PubMed

Insights

High expression of human endogenous retrovirus K(HML-2) (HERV-K(HML-2)) impairs cortical neuron development. This effect is cell-type-specific and mediated by NTRK3, revealing a role in neuronal differentiation.

Area of Science:

  • Neuroscience
  • Genetics
  • Developmental Biology

Background:

  • The functions and disease links of human endogenous retroviruses (HERVs) remain largely unknown.
  • HERV-K(HML-2) is implicated in neurotoxicity, but its precise role and mechanisms are unclear.

Purpose of the Study:

  • To investigate the physiological roles of HERV-K(HML-2) in neuronal differentiation.
  • To elucidate the mechanistic basis of HERV-K(HML-2)'s impact on neuronal development.

Main Methods:

  • Utilized CRISPR engineering in a human pluripotent stem cell system to modulate HERV-K(HML-2) expression.
  • Assessed effects on cortical neuron development, dopaminergic neuron differentiation, and forebrain organoid formation.
  • Analyzed gene expression changes, including NTRK3 and neurodegeneration-related genes.

Main Results:

  • Elevated HERV-K(HML-2) transcription negatively impacts cortical neuron development and function.
  • These effects are specific to cortical neurons, with dopaminergic neurons showing no impact.
  • High HERV-K(HML-2) levels alter cortical layer formation and upregulate NTRK3 expression.
  • NTRK3 activation mimics HERV-K(HML-2) induction, and reducing NTRK3 rescues differentiation defects.

Conclusions:

  • HERV-K(HML-2) plays a cell-type-specific role in cortical neuron development.
  • NTRK3 is a key mediator of HERV-K(HML-2)'s detrimental effects on cortical neurons.
  • Findings provide insights into the biological functions of HERVs in the developing brain.
Keywords:
CRISPRHERVNTRK3Neurotrophic Tyrosine Receptor Kinase 3endogenous retrovirusforebrain orgnoidinfluencing cortical neuronal developmentretrotransposon

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