7-Dehydrocholesterol-derived oxysterols cause neurogenic defects in Smith-Lemli-Opitz syndrome
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.
-
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.
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
© 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.
Metrics
-
- 1,124
- views
-
- 199
- downloads
-
- 12
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Neuroscience
Combining individual actions into sequences is a hallmark of everyday activities. Classical theories propose that the motor system forms a single specification of the sequence as a whole, leading to the coarticulation of the different elements. In contrast, recent neural recordings challenge this idea and suggest independent execution of each element specified separately. Here, we show that separate or coarticulated sequences can result from the same task-dependent controller, without implying different representations in the brain. Simulations show that planning for multiple reaches simultaneously allows separate or coarticulated sequences depending on instructions about intermediate goals. Human experiments in a two-reach sequence task validated this model. Furthermore, in co-articulated sequences, the second goal influenced long-latency stretch responses to external loads applied during the first reach, demonstrating the involvement of the sensorimotor network supporting fast feedback control. Overall, our study establishes a computational framework for sequence production that highlights the importance of feedback control in this essential motor skill.
-
- Neuroscience
Neuropathic pain (NP) is caused by a lesion or disease of the somatosensory system and is characterized by abnormal hypersensitivity to stimuli and nociceptive responses to non-noxious stimuli, affecting approximately 7–10% of the general population. However, current first-line drugs like non-steroidal anti-inflammatory agents and opioids have limitations, including dose-limiting side effects, dependence, and tolerability issues. Therefore, developing new interventions for the management of NP is urgent. In this study, we discovered that the high-frequency terahertz stimulation (HFTS) at approximately 36 THz effectively alleviates NP symptoms in mice with spared nerve injury. Computational simulation suggests that the frequency resonates with the carbonyl group in the filter region of Kv1.2 channels, facilitating the translocation of potassium ions. In vivo and in vitro results demonstrate that HFTS reduces the excitability of pyramidal neurons in the anterior cingulate cortex likely through enhancing the voltage-gated K+ and also the leak K+ conductance. This research presents a novel optical intervention strategy with terahertz waves for the treatment of NP and holds promising applications in other nervous system diseases.