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Temporal transcriptomic changes during neurodevelopment in a mouse model of Smith-Lemli-Opitz syndrome
Amy Li1, Hideaki Tomita1, Libin Xu1
1Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle, WA 98195, USA.
The Journal of Steroid Biochemistry and Molecular Biology
|January 8, 2026
Summary
Smith-Lemli-Opitz syndrome (SLOS), a cholesterol disorder, shows altered gene expression in developing brains. This study reveals key developmental pathways affected by Dhcr7 gene loss, impacting neurogenesis and synaptogenesis.
Area of Science:
- Genetics and Developmental Biology
- Neuroscience
- Biochemistry
Background:
- Smith-Lemli-Opitz syndrome (SLOS) is a genetic disorder of cholesterol biosynthesis, caused by mutations in the DHCR7 gene.
- SLOS leads to reduced cholesterol and accumulation of 7-dehydrocholesterol, resulting in neurodevelopmental and behavioral issues.
- Temporal gene expression changes in the developing brain during SLOS have not been comprehensively studied.
Purpose of the Study:
- To investigate the temporal gene expression alterations in the developing brain of mice lacking the Dhcr7 gene.
- To identify affected signaling pathways and biological processes during critical developmental stages.
Main Methods:
- Transcriptomic analysis of whole brains from wild-type (WT) and Dhcr7-knockout (Dhcr7-KO) mice at embryonic days E12.5, E14.5, E16.5, and postnatal day PND0.
- Pathway and Gene Ontology (GO) term enrichment analyses.
- In vitro neurogenesis experiments using isolated GABAergic neuronal precursors.
Main Results:
- Dhcr7 gene downregulation and altered cholesterol biosynthesis genes were observed in Dhcr7-KO brains across all time points.
- Early embryonic development (E12.5) showed significant impacts on Hippo, Wnt, and TGF-β signaling pathways, alongside neurogenesis-related GO terms.
- Later developmental stages (E16.5, PND0) revealed significant alterations in synaptogenesis pathways, including cholinergic, glutamatergic, and GABAergic synapses.
- In vitro studies confirmed that Dhcr7 deficiency reduces GABAergic neuronal precursor proliferation and causes premature neurogenesis.
Conclusions:
- Loss of Dhcr7 function profoundly impacts temporal gene expression in the developing brain, affecting crucial developmental pathways.
- The findings highlight distinct temporal effects on neurogenesis and synaptogenesis, providing insights into SLOS pathogenesis.
- These results offer a foundation for understanding the molecular mechanisms underlying SLOS neurodevelopmental defects.
