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7-dehydrocholesterol efficiently supports Ret signaling in a mouse model of Smith-Opitz-Lemli syndrome
Myriam Gou-Fàbregas1, Anna Macià1, Carlos Anerillas1
1Department of Experimental Medicine, Universitat de Lleida/Institut de Recerca Biomèdica de Lleida (IRB Lleida), Spain.
Abstract:
Smith-Lemli-Opitz syndrome (SLOS) is a rare disorder of cholesterol synthesis. Affected individuals exhibit growth failure, intellectual disability and a broad spectrum of developmental malformations. Among them, renal agenesis or hypoplasia, decreased innervation of the gut, and ptosis are consistent with impaired Ret signaling. Ret is a receptor tyrosine kinase that achieves full activity when recruited to lipid rafts. Mice mutant for Ret are born with no kidneys and enteric neurons, and display sympathetic nervous system defects causing ptosis. Since cholesterol is a critical component of lipid rafts, here we tested the hypothesis of whether the cause of the above malformations found in SLOS is defective Ret signaling owing to improper lipid raft composition or function. No defects consistent with decreased Ret signaling were found in newborn Dhcr7(-/-) mice, or in Dhcr7(-/-) mice lacking one copy of Ret. Although kidneys from Dhcr7(-/-) mice showed a mild branching defect in vitro, GDNF was able to support survival and downstream signaling of sympathetic neurons. Consistently, GFRα1 correctly partitioned to lipid rafts in brain tissue. Finally, replacement experiments demonstrated that 7-DHC efficiently supports Ret signaling in vitro. Taken together, our findings do not support a role of Ret signaling in the pathogenesis of SLOS.
Insights
Smith-Lemli-Opitz syndrome (SLOS) is a cholesterol synthesis disorder. This study found that defective Ret signaling is not the cause of SLOS-related developmental malformations.
Area of Science:
- Biochemistry
- Developmental Biology
- Genetics
Background:
- Smith-Lemli-Opitz syndrome (SLOS) is a rare genetic disorder affecting cholesterol synthesis.
- SLOS patients exhibit growth failure, intellectual disability, and developmental malformations, potentially linked to impaired Ret signaling.
- Ret signaling requires recruitment to lipid rafts, which are cholesterol-dependent membrane microdomains.
Purpose of the Study:
- To investigate whether defective Ret signaling due to altered lipid raft function causes developmental malformations in Smith-Lemli-Opitz syndrome.
- To determine if cholesterol precursor 7-dehydrocholesterol (7-DHC) can rescue Ret signaling defects.
Main Methods:
- Analysis of Ret signaling in Dhcr7(-/-) mice, a model for SLOS.
- In vitro studies assessing Ret signaling, lipid raft localization, and neuron survival.
- Experiments involving cholesterol precursor replacement.
Main Results:
- Newborn Dhcr7(-/-) mice showed no defects consistent with decreased Ret signaling.
- Kidney development in Dhcr7(-/-) mice exhibited only mild defects in vitro, with Ret signaling supported by GDNF.
- 7-dehydrocholesterol (7-DHC) demonstrated efficient support of Ret signaling in vitro.
Conclusions:
- The findings do not support a role for defective Ret signaling in the pathogenesis of Smith-Lemli-Opitz syndrome.
- Altered lipid raft composition or function in SLOS does not appear to impair Ret signaling.
- Developmental abnormalities in SLOS likely stem from mechanisms other than compromised Ret pathway activity.
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