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.

Highlights

  • The GDNF family ligands (GFLs) constitute a group of neurotrophic factors (GDNF, NRTN, PSPN, ARTN) that regulate several aspects of the developing nervous and genito-urinary systems[7]

  • In the present work we examined the hypothesis of whether suboptimal Ret signaling could explain some of the developmental abnormalities found in Smith–Lemli–Opitz syndrome (SLOS) patients

  • Such hypothesis was formulated based on the overlapping phenotypes of SLOS patients and Ret mutant mice, and the observation that lipid rafts are critical for proper Ret signaling

Read more

Summary

Introduction

The GDNF family ligands (GFLs) constitute a group of neurotrophic factors (GDNF, NRTN, PSPN, ARTN) that regulate several aspects of the developing nervous and genito-urinary systems[7]. Stimulation by GFLs prompts recruitment of Ret to lipid rafts, where the GFL-GFRα-Ret ternary complex interacts with Src family kinases to elicit maximal biological responses[8]. Critical components of Ret signaling including GFRα 1 or Src family kinases from knockout mice partitioned to the lipid raft fraction in flotation gradients, suggesting that 7-DHC allows formation of lipid rafts that efficiently support Ret signaling. In support with this notion, removal of cholesterol followed by replenishment with 7-DHC efficiently supported GDNF-mediated phosphorylation of Akt in MG87 fibroblasts cultured in the absence of cholesterol.

Objectives
Methods
Results
Conclusion
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call