7-Dehydrocholesterol-derived oxysterols cause neurogenic defects in Smith-Lemli-Opitz syndrome
- University of Washington, United States
- 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.
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7-Dehydrocholesterol-derived oxysterols cause neurogenic defects in Smith-Lemli-Opitz syndromeDryad Digital Repository, doi: 10.5061/dryad.zw3r2287f.
Article and author information
Author details
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.
Reviewing Editor
- Anita Bhattacharyya, University of Wisconsin, Madison, United States
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.
Version history
- Preprint posted: February 1, 2021 (view preprint)
- Received: February 1, 2021
- Accepted: September 15, 2022
- Accepted Manuscript published: September 16, 2022 (version 1)
- 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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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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