Related Experiment Videos
Pathogenesis of malformations in a rodent model for Smith-Lemli-Opitz syndrome
D B Dehart1, L Lanoue, G S Tint
1Department of Cell Biology and Anatomy, University of North Carolina at Chapel Hill 27599-7090, USA.
Abstract:
The fact that Smith-Lemli-Opitz syndrome (SLOS), a syndrome comprising major malformations involving a number of organ systems, results from an abnormality in cholesterol biosynthesis, was discovered only recently. Utilizing a drug (BM 15.766) to inhibit the same step in cholesterol biosynthesis as is abnormal in those affected with SLOS, we have developed a rat model that presents with abnormalities observed as early as gestational day 12 that appear to be consistent with some of those subsequent malformations that comprise the human syndrome. Abnormalities of the brain and face include deficiency in the midline region of the upper face, narrowing of the forebrain hemispheres and of the cerebral aqueduct, and deficiency in the developing lower jaw. Associated pathogenesis, as observed on gestational day 11 in histological sections and with scanning electron microscopy, involves abnormal cell populations at the rim of the developing forebrain and in the alar plate of the lower midbrain and hind-brain. The affected cells appear abnormally rounded up, having apparently lost their normal cell contacts. The potential basis for the selective vulnerability of this cell population and the impact of its vulnerability relative to subsequent dysmorphogenesis is discussed.
Insights
Smith-Lemli-Opitz syndrome (SLOS) arises from cholesterol biosynthesis defects. A new rat model using BM 15.766 drug mimics SLOS, revealing early brain and facial malformations.
Area of Science:
- Developmental Biology
- Biochemistry
- Teratology
Background:
- Smith-Lemli-Opitz syndrome (SLOS) is a genetic disorder characterized by major malformations across multiple organ systems.
- Recent research links SLOS to abnormalities in cholesterol biosynthesis.
- Understanding the pathogenesis of SLOS is crucial for developing therapeutic strategies.
Purpose of the Study:
- To develop a rat model for Smith-Lemli-Opitz syndrome (SLOS) by inhibiting cholesterol biosynthesis.
- To investigate the early developmental abnormalities associated with this inhibition.
- To elucidate the cellular mechanisms underlying SLOS-related dysmorphogenesis.
Main Methods:
- Utilized the drug BM 15.766 to inhibit cholesterol biosynthesis at the same step affected in SLOS.
- Observed rat embryos at gestational day 12 for malformations.
- Performed histological analysis and scanning electron microscopy on gestational day 11 embryos to examine cellular pathogenesis.
Main Results:
- The BM 15.766 treated rats exhibited malformations consistent with human SLOS, including midline facial defects, forebrain abnormalities, and jaw deficiencies.
- Early developmental abnormalities were noted as early as gestational day 12.
- Histological examination revealed abnormal cell populations with disrupted cell contacts in the developing brain.
Conclusions:
- The developed rat model effectively recapitulates key features of Smith-Lemli-Opitz syndrome.
- Inhibition of cholesterol biosynthesis leads to specific cellular defects that contribute to craniofacial and brain malformations.
- Further research into the vulnerable cell populations may provide insights into SLOS pathogenesis and potential interventions.