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  1. Reviewer #3 (Public Review):

    Mutations in DHCR7, a key enzyme in cholestrol biosysnthesis have been shown to result in Smith-Lemili-Opitz syndrome. However, the mechanism by which loss of this enzyme alters brain development has not been resolved.

    In this study, the authors demonstrate that DHCR7 depletion results in depletion of cholestrol in the brain and also the accumulation of the substrate 7 dehydrocholestrol. These observations are conserved in both the brain of DHCR7 knockout mice as well as patient derived iPSC differentiated in vitro.

    The authors present evidence that the developmental defects in the brain are a consequence of accelerated differentiation of NSC into neural cells. These defects could be recapitulated by the addition of 7DHC metabolites on wild type cells.

    Throughout the manuscript, the authors demonstrate that their findings are conserved between DHC7 k/o mice and patient derived iPSC for SLO syndrome.

    To explain the mechanism underlying the cellular phenotypes described, authors propose that the accumulated 7DHC metabolites bind to and activate the glucocorticoid receptor leading to transcriptional activity.

    Overall this paper attempts to provide a comprehensive mechanistic explanation for the neurodevelopmental phenotype arising from the loss of a lipid metabolizing enzyme.

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  2. Reviewer #2 (Public Review):

    The authors study in this report enzymes and sterols implicated in SLOS. They have performed in-vitro and in-vivo experiments. They show that a major metabilte, DHCEO, mediates the effects in neurogenesis and neuronal localisation. They have studied the mechanism of action of this effect. Pharmacological intervention can rescue the negative effects.

    The Introduction is clearly written and provides nice background information on the disorder, the implicated enzymes and sterols.

    The authors analyse extensively cell survival, neurogenesis, proliferation, several progenitor markers in both cell culture and in the Dhcr7-KO mice. In vivo they study several developmental stages.

    They have generated SLOS hiPSCs and studied those too.

    The analysis of sterol and oxysterol levels in WT vs Dhcr7-KO is very interesting and informative.

    The Dhcr7 shRNA experiments show clear effects on neurogenesis and cycling precursor cell population number.

    The RNAseq experiments also give interesting gene expression results and possible signaling pathways involved.

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  3. Reviewer #1 (Public Review):

    The study is focused on neural deficits in Smith-Lemli-Opitz syndrome (SLOS) that is caused by loss of function of 3b-hydroxysterol-D7 -reductase (DHCR7) and results in lower cholesterol. Individuals with SLOS have cognitive impairment and the authors use mouse models and human iPSCs to investigate the effects of the SLOS mutation on neural progenitor proliferation and neurogenesis. Data show that the loss of DHCR7 leads to premature differentiation of cortical progenitors and altered cortical development. However, the work offers little mechanistic insight.

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  4. Evaluation Summary:

    This paper will be of interest to developmental biologists and neuroscientists as it aims to resolve the unknown mechanism by which loss of a key enzyme in cholesterol biosynthesis results in neurodevelopmental defects. It provides a conceptual framework for understanding how altered lipid metabolism can impact brain development. Many of the key claims of the paper are well-supported, but reasonable alternative explanations remain.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

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