title: 7-dehydrocholesterol efficiently supports Ret signaling in a mouse model of Smith-Opitz-Lemli syndrome.
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.
authors.affiliation: Department of Experimental Medicine, Universitat de Lleida/Institut de Recerca Biomèdica de Lleida (IRB Lleida), Spain.
authors.forename: Myriam
authors.initials: M
authors.lastname: Gou-Fàbregas
authors.affiliation: Department of Experimental Medicine, Universitat de Lleida/Institut de Recerca Biomèdica de Lleida (IRB Lleida), Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Macià
authors.affiliation: Department of Experimental Medicine, Universitat de Lleida/Institut de Recerca Biomèdica de Lleida (IRB Lleida), Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Anerillas
authors.affiliation: Department of Experimental Medicine, Universitat de Lleida/Institut de Recerca Biomèdica de Lleida (IRB Lleida), Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Vaquero
authors.affiliation: Metabolomics Service, IRB Lleida, Rovira Roure, 80, Lleida 25198, Spain.
authors.forename: Mariona
authors.initials: M
authors.lastname: Jové
authors.affiliation: Departments of Internal Medicine (Renal Division) and Pathology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Jain
authors.affiliation: Department of Experimental Medicine, Universitat de Lleida/Institut de Recerca Biomèdica de Lleida (IRB Lleida), Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Ribera
authors.affiliation: Department of Experimental Medicine, Universitat de Lleida/Institut de Recerca Biomèdica de Lleida (IRB Lleida), Spain.
authors.forename: Mario
authors.initials: M
authors.lastname: Encinas
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D003684:Dehydrocholesterols / Q000494:pharmacology*; D004195:Disease Models, Animal; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000378:metabolism; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D019082:Smith-Lemli-Opitz Syndrome / Q000188:drug therapy* / Q000378:metabolism*
chemical_list: D003684:Dehydrocholesterols; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D002784:Cholesterol; C016705:7-dehydrocholesterol; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019995:7-dehydrocholesterol reductase; D051096:Proto-Oncogene Proteins c-ret; C494999:Ret protein, mouse