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Density Lipoprotein Receptor (Low Density Lipoprotein Receptor Gene Family/Triacylglycerol Metabolism/Body Weight/Adipose Tissue/Homologous Recombination) PHILIP K

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Density Lipoprotein Receptor (Low Density Lipoprotein Receptor Gene Family/Triacylglycerol Metabolism/Body Weight/Adipose Tissue/Homologous Recombination) PHILIP K Proc. Natl. Acad. Sci. USA Vol. 92, pp. 8453-8457, August 1995 Medical Sciences Normal plasma lipoproteins and fertility in gene-targeted mice homozygous for a disruption in the gene encoding very low density lipoprotein receptor (low density lipoprotein receptor gene family/triacylglycerol metabolism/body weight/adipose tissue/homologous recombination) PHILIP K. FRYKMAN*, MICHAEL S. BROWN*, ToKuo YAMAMOTOt, JOSEPH L. GOLDSTEIN*, AND JOACHIM HERZ* *Department of Molecular Genetics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75235-9046; and tTohoku University Gene Research Center, Sendai 981, Japan Contributed by Joseph L. Goldstein, June 1, 1995 ABSTRACT The very low density lipoprotein (VLDL) homologous recombination in embryonic stem (ES) cells (8, 9) receptor is a recently cloned member of the low density to produce mice that lack VLDLR. Males and females ho- lipoprotein (LDL) receptor family that mediates the binding mozygous for the disrupted VLDLR allele were viable and and uptake of VLDL when overexpressed in animal cells. Its fertile, producing litters of normal size. The lipoprotein pro- sequence is 94% identical in humans and rabbits and 84% files of the VLDLR knockout mice showed no difference from identical in humans and chickens, implying a conserved wild-type littermates. Extensive studies failed to reveal any function. Its high level expression in muscle and adipose tissue significant phenotype in homozygous knockout mice, with the suggests a role in VLDL triacylglycerol delivery. Mutations in sole exception that the animals were somewhat smaller and the chicken homologue cause female sterility, owing to im- leaner than their wild-type littermates. paired VLDL and vitellogenin uptake during egg yolk forma- tion. We used homologous recombination in mouse embryonic stem cells to produce homozygous knockout mice that lack METHODS immunodetectable VLDL receptors. Homozygous mice ofboth Assays and Materials. Lipoprotein analysis was performed sexes were viable and normally fertile. Plasma levels of cho- by FPLC on a Superose 6 column (10). Cholesterol and lesterol, triacylglycerol, and lipoproteins were normal when triacylglycerols were determined with assay kits from Boeh- the mice were fed normal, high-carbohydrate, or high-fat diets. ringer Mannheim and Sigma, respectively. Insulin, glucose, and The sole abnormality detected was a modest decrease in body free fatty acids were measured in the laboratory of Dr. J. D. weight, body mass index, and adipose tissue mass as deter- McGarry of this institution by use of a Linco rat insulin RIA mined by the weights ofepididymal fat pads. We conclude that kit (no. RI-13K; Linco Research, St. Louis), Beckman Glucose the VLDL receptor is not required for VLDL clearance from Analyzer II, and free fatty acid Half Micro test kit (Boehringer plasma or for ovulation in mice. Mannheim), respectively. A peptide corresponding to the carboxyl-terminal 10 amino acids of the mouse VLDLR (Ser- The very low density lipoprotein (VLDL) receptor (VLDLR) Val-Val-Ser-Thr-Asp-Asp-Asp-Leu-Ala) was coupled to key- is the member of the low density lipoprotein (LDL) receptor hole limpet hemocyanin (5) and used to immunize rabbits by (LDLR) gene family that most closely resembles the LDLR (1, subcutaneous injection with Freund's adjuvant. A rabbit poly- 2). The VLDLR received its name because its overexpression clonal antibody directed against amino acids 1-724 of the enhances the binding and uptake of apoE-containing lipopro- human VLDLR was kindly provided by Kittie Wyne and Helen teins (VLDL and ,B-VLDL), but not apoB-100-containing Hobbs of this Department. lipoproteins (LDL), in cultured cells (1, 3, 4). A tissue survey Diets. The normal mouse diet (Teklad 6% mouse/rat diet showed widespread expression of VLDLR mRNA, with high- 7002 from Harlan Teklad Premier Laboratory Diets, Mad- est levels in muscle and adipose tissue and only trace amounts ison, WI) contained 6% fat, 24% protein, and 5% fiber by in the liver (2, 5). These data suggested that the VLDLR might weight. The high-carbohydrate diet (modified no. 960236; be involved in the transport of triacylglycerol-rich VLDL to its ICN) contained 68% sucrose, 18% casein, and 8% cotton main sites of metabolism, muscle and adipose tissue (1, 5). seed oil by weight. The cholesterol/atherogenic diet (mod- Recently, the chicken homologue of the VLDLR was cloned ified no. 900865; ICN) contained 40% butter, 20% casein, and found to be identical to the oocyte vitellogenin receptor 20% sucrose, 5.3% cholesterol, and 2% sodium cholate by (6, 7). The chicken vitellogenin/VLDL receptor has 84% weight. Animals were weighed on a Sartorius LC 4800 POAC amino acid identity to the human VLDLR, and it transports balance. both VLDL and vitellogenin into the yolk of developing cDNA Cloning. A mouse heart cDNA library in AZapII oocytes. In chickens the VLDLR gene is located on the X (Stratagene) was screened with a 2.6-kb Hindlll fragment of chromosome. In birds females are the heterogametic sex and the rabbit VLDLR cDNA (1). The resulting 3-kb mouse cDNA have only one X-equivalent chromosome. Hens hemizygous encoded a sequence that extended from exon 2 to the polya- for a mutated vitellogenin receptor are infertile and hyperlip- denylylation site. The encoded sequence showed 94% identity idemic secondary to the lack of lipoprotein transport into with the human amino acid sequence. oocytes, whereas heterozygous roosters are phenotypically Construction ofTargeting Vector. A 12-kb fragment encod- normal (7). ing introns 3-17 of the mouse VLDLR gene was enriched by In humans the VLDLR is encoded on chromosome 9 (2). Its sucrose density ultracentrifugation of Bgl II-digested 129Sv function in the body is unclear. To study the physiological mouse genomic DNA, cloned into ADashII (Stratagene), and function of the VLDLR in mammals, we used the technique of isolated by plaque screening using the 2.6-kb Hindlll fragment The publication costs of this article were defrayed in part by page charge Abbreviations: BMI, body mass index; ES cells, embryonic stem cells; payment. This article must therefore be hereby marked "advertisement" in LDL, low density lipoprotein; LDLR, LDL receptor; VLDL, very low accordance with 18 U.S.C. §1734 solely to indicate this fact. density lipoprotein; VLDLR, VLDL receptor. 8453 Downloaded by guest on September 25, 2021 8454 Medical Sciences: Frykman et al. Proc. Natl. Acad. Sci. USA 92 (1995) of the rabbit VLDLR cDNA. A replacement-tylpe targeting carried the disrupted VLDLR allele through the germline. All vector (11) was constructed (Fig. 1). The short arm of the experiments were performed with the F2 or F3 generation vector (1 kb) was amplified by PCR using Pfu polymerase descendants, which were hybrids between C57BL/6J and (Stratagene) from the Pst I site in intron 4 to the cysteine-161 129Sv mice. codon in exon 5 of the mouse VLDLR gene. TIhe long arm Blot Hybridization of Genomic DNA. Tail DNA was pre- extending from the third nucleotide position of the proline-262 pared by proteinase K digestion, phenol/chloroform extrac- codon in exon 5 to the Bgl II site (8.8 kb) was pr-epared by a tion, and ethanol precipitation (14). For Southern blotting, 10 combination of PCR cloning and direct subcloniing of a 7-kb ,ug of genomic DNA was loaded onto each lane after digestion Kpn I-Bgl II fragment into pGEM-3Zf(+) (Promelga), deleting with EcoRI. After hybridization with a randomly 32P-labeled residues 162 to 262 of exon 5. The Pol2sneobpAI expression probe (1-2 x 106 cpm/ml; see legend to Fig. 1) at 65°C in cassette (12) was inserted into the deletion created in exon 5, Rapid-hyb buffer (Amersham) for 3-6 hr, the blot was washed and two copies of the herpes simplex virus thymiidine kinase for 15 min in 2x SSC/0.5% SDS (15) at room temperature and gene (12) were inserted in tandem at the 5' end of the short then for 30 min in 0.2x SSC/0.1% SDS at 65°C. arm of the targeting vector. ES Cell Culture. Mouse ES cells (JH-1) were cultured on RESULTS leukemia inhibitory factor-producing STO feeder cells (13). Approximately 2 x 107 cells were electroporated (275 V, 330 To disrupt the VLDLR gene in murine ES cells, we con- ,F; GIBCO/BRL electroporator) with a Sal I-lin earized tar- structed a targeting vector of the replacement type (11) with geting vector (25 ,ug/ml) and seeded onto irradiiated feeder a neo cassette inserted into exon 5 of the VLDLR gene, layers. After selection with G418 (190 jig/ml) and 1-(2-deoxy- disrupting the reading frame (Fig. 1). The linearized targeting 2-fluoro-f3-D-arabinofuranosyl)-5-iodouracil (FIA,U, 0.25 ,uM; construct was electroporated into ES cells, which were then Bristol-Myers Squibb), recombinant clones were iidentified by placed under positive and negative selection (13). Homologous PCR (13) using primers 3 and 4 (primer 3, locatted in the 3' recombinants were detected by PCR and confirmed by South- untranslated region of the neo cassette, 5'-CCT(CGTGCTT- ern analysis ofEcoRI-digested ES cell genomic DNA with the TACGGTATCGCCGCTC-3'; primer 4, located in intron 4, probe shown in Fig. 1. Recombinant ES cell clones were 5 '-CCCTGGAGAAAATCTGCGGGTTAAATA-3'). Ho- expanded and microinjected into C57BL/6J blastocysts by mologous recombination was verified by Southern analysis standard techniques (12). Several male chimeras derived from after EcoRI digestion and probing with a 0.8-kb genomic independently targeted ES cell clones transmitted the dis- fragment 5' of the targeting construct (Fig. 1). Eigght indepen- rupted gene through the germline as determined by Southern dent ES cell clones containing a disrupted VLDLI . allele were blotting (data not shown). injected into C57BL/6J blastocysts, yielding a total of 34 A total of 26 matings between VLDLR +/- mice yielded chimeric males whose coat color (agouti) indicatted a contri- 200 offspring, comprising 50 +/+, 103 +/-, and 47 -/- for bution of ES cells ranging from 20% to 95%.
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