Journal
ELIFE
Volume 11, Issue -, Pages -Publisher
eLIFE SCIENCES PUBL LTD
DOI: 10.7554/eLife.67141
Keywords
smith-lemli-opitz syndrome; 7-dehydrocholesterol; oxysterol; neurogenesis; glucocorticoid receptor; cortical development; Human; Mouse
Categories
Funding
- National Institutes of Health (NIH) [R01HD092659]
- Smith-Lemli-Opitz/RSH Foundation
- University of Washington (UW) Environmental Pathology/ Toxicology Training Program [NIH T32 ES007032]
- UW Pharmacological Sciences Training Program [NIH T32 GM007750]
- Institute of Translational Health Sciences TL1 Program [NIH TL1 TR002318]
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Deficient DHCR7 in SLOS leads to cholesterol deficiency and accumulation of 7-DHC. This study reveals that loss of DHCR7 causes accumulation of 7-DHC-derived oxysterol metabolites, premature neurogenesis, and depletion of cortical precursor pool. The major oxysterol, DHCEO, mediates these effects through crosstalk between GR and TrkB.
Defective 3 beta-hydroxysterol-delta(7) -reductase (DHCR7) in the developmental disorder, Smith-Lemli-Opitz syndrome (SLOS), results in a 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, 3 beta,5 alpha-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.
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