7-Dehydrocholesterol-derived oxysterols cause neurogenic defects in Smith-Lemli-Opitz syndrome

  1. Hideaki Tomita
  2. Kelly M Hines
  3. Josi M Herron
  4. Amy Li
  5. David W Baggett
  6. Libin Xu  Is a corresponding author
  1. University of Washington, United States
  2. University of Georgia, United States

Abstract

Defective 3b-hydroxysterol-D7-reductase (DHCR7) in the developmental disorder, Smith-Lemli-Opitz syndrome (SLOS), results in deficiency in cholesterol and accumulation of its precursor, 7-dehydrocholesterol (7-DHC). Here, we show that loss of DHCR7 causes accumulation of 7-DHC-derived oxysterol metabolites, premature neurogenesis from murine or human cortical neural precursors, and depletion of the cortical precursor pool, both in vitro and in vivo. We found that a major oxysterol, 3b,5a-dihydroxycholest-7-en-6-one (DHCEO), mediates these effects by initiating crosstalk between glucocorticoid receptor (GR) and neurotrophin receptor kinase TrkB. Either loss of DHCR7 or direct exposure to DHCEO causes hyperactivation of GR and TrkB and their downstream MEK-ERK-C/EBP signaling pathway in cortical neural precursors. Moreover, direct inhibition of GR activation with an antagonist or inhibition of DHCEO accumulation with antioxidants rescues the premature neurogenesis phenotype caused by the loss of DHCR7. These results suggest that GR could be a new therapeutic target against the neurological defects observed in SLOS.

Data availability

Raw RNA sequencing data has been deposited at Dryad at https://doi.org/10.5061/dryad.zw3r2287f. This data was used to generate Figure 7 and Table S5.

The following data sets were generated

Article and author information

Author details

  1. Hideaki Tomita

    Department of Medicinal Chemistry, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Kelly M Hines

    Department of Chemistry, University of Georgia, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Josi M Herron

    Department of Medicinal Chemistry, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Amy Li

    Department of Medicinal Chemistry, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7732-3540
  5. David W Baggett

    Department of Medicinal Chemistry, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Libin Xu

    Department of Medicinal Chemistry, University of Washington, Seattle, United States
    For correspondence
    libinxu@uw.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1021-5200

Funding

National Institutes of Health (R01 HD092659)

  • Libin Xu

National Institutes of Health (T32 ES007032)

  • Josi M Herron

National Institutes of Health (T32 GM007750)

  • Amy Li

National Institutes of Health (TL1 TR002318)

  • Amy Li

Smith-Lemli-Opitz/RSH Foundation (Research grant)

  • Libin Xu

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#4350-01) of the University of Washington.

Reviewing Editor

  1. Anita Bhattacharyya, University of Wisconsin, Madison, United States

Publication history

  1. Preprint posted: February 1, 2021 (view preprint)
  2. Received: February 1, 2021
  3. Accepted: September 15, 2022
  4. Accepted Manuscript published: September 16, 2022 (version 1)
  5. Version of Record published: September 28, 2022 (version 2)

Copyright

© 2022, Tomita et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Hideaki Tomita
  2. Kelly M Hines
  3. Josi M Herron
  4. Amy Li
  5. David W Baggett
  6. Libin Xu
(2022)
7-Dehydrocholesterol-derived oxysterols cause neurogenic defects in Smith-Lemli-Opitz syndrome
eLife 11:e67141.
https://doi.org/10.7554/eLife.67141

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