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

Abstract
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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

1. Xu L
2. Tomita H
3. Herron J
(2021) 7-Dehydrocholesterol-derived oxysterols cause neurogenic defects in Smith-Lemli-Opitz syndrome
Dryad Digital Repository, doi: 10.5061/dryad.zw3r2287f.

https://dx.doi.org/10.5061/dryad.zw3r2287f

Article and author information

Author details

Hideaki Tomita

Department of Medicinal Chemistry, University of Washington, Seattle, United States

Competing interests
The authors declare that no competing interests exist.
Kelly M Hines

Department of Chemistry, University of Georgia, Seattle, United States

Competing interests
The authors declare that no competing interests exist.
Josi M Herron

Department of Medicinal Chemistry, University of Washington, Seattle, United States

Competing interests
The authors declare that no competing interests exist.
Amy Li

Department of Medicinal Chemistry, University of Washington, Seattle, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-7732-3540
David W Baggett

Department of Medicinal Chemistry, University of Washington, Seattle, United States

Competing interests
The authors declare that no competing interests exist.
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.

"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.

Copyright

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.