biostudies-literatureTomita HNICHD NIH HHSNCATS NIH HHSNIEHS NIH HHSNational Institutes of HealthNIH HHSNIGMS NIH HHSSmith-Lemli-Opitz/RSH Foundatione67141https://www.ebi.ac.uk/biostudies/studies/S-EPMC9519149biostudies-literatureUnknown11Defective 3β-hydroxysterol-Δ⁷ -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 <i>DHCR7</i> 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, 3β,5α-dihydroxycholest-7-en-6-one (DHCEO), mediates these effects by initiating crosstalk between glucocorticoid receptor (GR) and neurotrophin receptor kinase TrkB. Either loss of <i>DHCR7</i> or direct exposure to DHCEO causes hyperactivation of GR and TrkB and their downstream MEK-ERK-C/EeLife7-Dehydrocholesterol-derived oxysterols cause neurogenic defects in Smith-Lemli-Opitz syndrome.PMC9519149T32 GM007750P30 ES007033R01 HD092659Research grantTL1 TR002318T32 ES007032Xu LHerron JMBaggett DWTomita HLi AHines KMfalse7-Dehydrocholesterol-derived oxysterols cause neurogenic defects in Smith-Lemli-Opitz syndrome.Defective 3β-hydroxysterol-Δ⁷ -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 <i>DHCR7</i> 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, 3β,5α-dihydroxycholest-7-en-6-one (DHCEO), mediates these effects by initiating crosstalk between glucocorticoid receptor (GR) and neurotrophin receptor kinase TrkB. Either loss of <i>DHCR7</i> or direct exposure to DHCEO causes hyperactivation of GR and TrkB and their downstream MEK-ERK-C/E2022-01-01T00:00:00Z2022 Sep2026-05-28T00:34:53.757Z2025-04-19T05:16:00.334ZS-EPMC95191493611178510.7554/eLife.67141