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Please use this identifier to cite or link to this item: http://hdl.handle.net/1942/22066

Title: 7-dehydrocholesterol efficiently supports Ret signaling in a mouse model of Smith-Opitz-Lemli syndrome
Authors: Gou-Fabregas, Myriam
Macia, Anna
Anerillas, Carlos
Vaquero, Marta
Jove, Mariona
Jain, Sanjay
Ribera, Joan
Encinas, Mario
Issue Date: 2016
Publisher: NATURE PUBLISHING GROUP
Citation: SCIENTIFIC REPORTS, 6 (Art N° 28534)
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, GFR alpha 1 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.
Notes: [Gou-Fabregas, Myriam; Macia, Anna; Anerillas, Carlos; Vaquero, Marta; Ribera, Joan; Encinas, Mario] Univ Lleida, Dept Expt Med, IRB Lleida, Lleida, Spain. [Jove, Mariona] IRB Lleida, Metabol Serv, Rovira Roure 80, Lleida 25198, Spain. [Jain, Sanjay] Washington Univ, Sch Med, Dept Internal Med, Div Renal, St Louis, MO 63110 USA. [Jain, Sanjay] Washington Univ, Sch Med, Dept Pathol, St Louis, MO 63110 USA. [Gou-Fabregas, Myriam] Hasselt Univ, Dept Morphol, BE-3590 Diepenbeek, Belgium. [Gou-Fabregas, Myriam] Hasselt Univ, Biomed Res Inst, BE-3590 Diepenbeek, Belgium.
URI: http://hdl.handle.net/1942/22066
DOI: 10.1038/srep28534
ISI #: 000378323800001
ISSN: 2045-2322
Category: A1
Type: Journal Contribution
Validation: ecoom, 2017
Appears in Collections: Research publications

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