title: SREBP-2-deficient and hypomorphic mice reveal roles for SREBP-2 in embryonic development and SREBP-1c expression.
abstract: Cholesterol and fatty acid biosynthesis are regulated by the sterol regulatory element-binding proteins (SREBPs), encoded by Srebf1 and Srebf2. We generated mice that were either deficient or hypomorphic for SREBP-2. SREBP-2 deficiency generally caused death during embryonic development. Analyses of Srebf2(-/-) embryos revealed a requirement for SREBP-2 in limb development and expression of morphogenic genes. We encountered only one viable Srebf2(-/-) mouse, which displayed alopecia, attenuated growth, and reduced adipose tissue stores. Hypomorphic SREBP-2 mice (expressing low levels of SREBP-2) survived development, but the female mice exhibited reduced body weight and died between 8 and 12 weeks of age. Male hypomorphic mice were viable but had reduced cholesterol stores in the liver and lower expression of SREBP target genes. Reduced SREBP-2 expression affected SREBP-1 isoforms in a tissue-specific manner. In the liver, reduced SREBP-2 expression nearly abolished Srebf1c transcripts and reduced Srebf1a mRNA levels. In contrast, adipose tissue displayed normal expression of SREBP target genes, likely due to a compensatory increase in Srebf1a expression. Our results establish that SREBP-2 is critical for survival and limb patterning during development. Reduced expression of SREBP-2 from the hypomorphic allele leads to early death in females and reduced cholesterol content in the liver, but not in adipose tissue.
authors.affiliation: Departments of Human Genetics David Geffen School of Medicine at the University of California, Los Angeles, CA 90095.
authors.forename: Laurent
authors.initials: L
authors.lastname: Vergnes
authors.affiliation: Departments of Human Genetics David Geffen School of Medicine at the University of California, Los Angeles, CA 90095.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Chin
authors.affiliation: Medicine, David Geffen School of Medicine at the University of California, Los Angeles, CA 90095.
authors.forename: Thomas
authors.initials: T
authors.lastname: de Aguiar Vallim
authors.affiliation: Medicine, David Geffen School of Medicine at the University of California, Los Angeles, CA 90095.
authors.forename: Loren G
authors.initials: LG
authors.lastname: Fong
authors.affiliation: Metabolic Disease Program, Sanford-Burnham Medical Research Institute, Orlando, FL 32827.
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Osborne
authors.affiliation: Departments of Human Genetics David Geffen School of Medicine at the University of California, Los Angeles, CA 90095 Medicine, David Geffen School of Medicine at the University of California, Los Angeles, CA 90095 Molecular Biology Institute, University of California, Los Angeles, CA 90095.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Young
authors.affiliation: Departments of Human Genetics David Geffen School of Medicine at the University of California, Los Angeles, CA 90095 Medicine, David Geffen School of Medicine at the University of California, Los Angeles, CA 90095 Molecular Biology Institute, University of California, Los Angeles, CA 90095 reuek@ucla.edu.
authors.forename: Karen
authors.initials: K
authors.lastname: Reue
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D050154:Adiposity / Q000235:genetics; D000483:Alleles; D000818:Animals; D002460:Cell Line; D047108:Embryonic Development / Q000235:genetics*; D005121:Extremities / Q000196:embryology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006706:Homeostasis / Q000235:genetics; D050356:Lipid Metabolism / Q000235:genetics; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D009154:Mutation; D012727:Sex Characteristics; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics* / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D014022:Tissue Survival / Q000235:genetics
chemical_list: D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2
keywords: cholesterol synthesis; gene regulation; sterol regulatory element-binding protein 1c; sterol regulatory element-binding protein 2