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Submaxillary Gland of the Mouse (Androgen Action/Hypertension/Recombinant Inbred Strains/Regulatory Genes) CAROL M

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Submaxillary Gland of the Mouse (Androgen Action/Hypertension/Recombinant Inbred Strains/Regulatory Genes) CAROL M Proc. Nati. Acad. Sci. USA Vol. 75, No. 11, pp. 5623-5626, November 1978 Genetics Location on chromosome 1 of Rnr, a gene that regulates renin in the submaxillary gland of the mouse (androgen action/hypertension/recombinant inbred strains/regulatory genes) CAROL M. WILSON*t, ERVIN G. ERDoS*t, JEAN D. WILSONtI, AND BENJAMIN A. TAYLOR§ Departments of *Pharmacology and tInternal Medicine, and tthe Eugene McDermott Center for Growth and Development, The University of Texas Southwestern Medical School, 5323 Harry Hines Boulevard, Dallas, Texas 75235; and §The Jackson Laboratory, Bar Harbor, Maine 04609 Communicated by P. Kusch, August 21, 1978 ABSTRACT Renin activity (EC 3.4.99.19) was measured in MATERIALS AND METHODS submaxillary gland extracts from four sets of recombinant inbred mouse strains. Recombination between Rnr, a gene that Animals. Inbred strains of mice were obtained from the mediates the susceptibility of submaxillary gland renin to in- Jackson Laboratory. BXD recombinant inbred strains were duction by androgen, and Dip-i, a chromosome 1 marker, was derived by brother-sister inbreeding, beginning with the F2 found in only 1 of 51 recombinant inbred strains, indicating that generation from the cross of C57BL/6J and DBA/2J inbred the two genes are closely linked on chromosome 1. Renin ac- mice (13). AKXL recombinant inbred strains were similarly tivity in androgen-treated female mice of all recombinant inbred derived from the cross of AKR/J and C57L/J (14), and SWXL strains resembled that of one or the other progenitor strains, as recombinant inbred strains the cross expected if a single gene is responsible. Documentation that a fyom of SWR/J and single gene can have major effects on renin in the submaxillary C57L/J (15) inbred mice. HP/Ei is a single recombinant inbred gland of the mouse implies that single gene differences might strain derived from AKR/J and C57BL/6J inbred mice (16). explain known variations in renin in other species. Sample Preparation and Assays. Eight-week-old female mice were treated with 2 mg of dihydrotestosterone in 0.2 ml Renin is a proteolytic enzyme (EC 3.4.99.19) that cleaves a of sesame oil (induced) or sesame oil alone (control) every other plasma protein substrate to release angiotensin I. Angiotensin day for one week. Submaxillary glands were removed, ho- I is subsequently converted to angiotensin II, a potent vaso- mogenized, and centrifuged for 60 min at 104,000 X g as pre- pressor agent. Regulation of plasma renin activity plays an viously described (11). Renin enzymatic activity in the super- important role in the maintenance of normal blood pressure natant fraction was assayed essentially as previously described under conditions such as sodium deprivation (1); moreover, (11). The final incubation mixture (63 ,ul) contained supernatant elevated renin levels in plasma constitute an important cause (0.02-50.ug protein), 4 mM EDTA, 1 mM o-phenanthroline, of hypertension in humans (2). The kidney is the primary source 1 mM diisopropylfluorophosphate, 13 mM 2,3-dimercap- of plasma renin. However, in some strains of mice, submaxillary topropanol, 50 mM Tris-HCl, and partially purified hog an- glands contain large amounts of renin, exceeding that of the giotensinogen containing the equivalent of 0.3 nmol of angio- kidney (3, 4). Submaxillary gland is tensin I (final pH 7.8). The supernatants had been preincubated renin present in higher at a protein concentration of 0.6-2 mg/ml for 15 min at 37'C concentration in males than in females and can be induced in in the presence of the o-phenanthroline/diisopropylfluoro- females by treatment with androgen (5-7). The submaxillary phosphate/2,3-dimercaptopropanol/Tris mixture to inhibit gland enzyme has been purified to homogeneity (8) and appears angiotensin I converting enzyme and angiotensinases. The re- indistinguishable from mouse kidney renin (9, 10). Using two action was initiated by adding aliquots of preincubated su- inbred strains of mice that differ widely in submaxillary gland pernatant to the substrate. After incubation of the final mixture renin activity, we have previously shown by segregation analysis at 37°C for 10 min, the reaction was stopped by freezing at that the susceptibility of submaxillary gland renin to induction -50°C, and the amount of angiotensin I generated was deter- by androgen is apparently mediated by a single gene (11). Al- mined by radioimmunoassay. Results are expressed as nmol though the possibility of variation in renin structure has not angiotensin I produced per min at 37°C. In some experiments, been excluded, this gene seems to regulate the synthesis of renin. samples from two different strains were mixed, either before We therefore propose to designate the gene renin regulator and or after preincubation, and assayed as described. the gene symbol Rnr.1 Rnrs and Rnrb are designated as symbols The supernatant fraction was analyzed for high or low renin for alleles carried by SWR/J and C57BL/10J, the high and low concentration by double diffusion versus antiserum to mouse reference strains, respectively. submaxillary gland renin as previously described (11), except In the current study we analyzed submaxillary gland extracts that 25-,ul samples from control animals were used. Epidermal from control and androgen-treated female mice of 24 additional growth factor was also estimated by immunodiffusion using inbred strains for renin. Four informative sets of recombinant 1O-.sl samples from either control or induced animals. Protein inbred mouse strains were identified and tested to confirm that was measured by the method of Lowry et al. (17) the induction of renin by androgen is determined by a single Reagents. Standard angiotensin I was obtained from Beck- gene and to locate this gene on the mouse linkage map. man. Antiserum to angiotensin I was the gift of T. F. Good- We have symbolized the gene that controls the regulation of renin The publication costs of this article were defrayed in part by page activity Rnr, in accordance with the terminology used by Paigen et charge payment. This article must therefore be hereby marked "ad- al. (12) for genes that are involved in the realization of f3-glucuron- vertisement" in accordance with 18 U. S. C. §1734 solely to indicate idase activity in mice. With this terminology, the structural gene for this fact. renin would be symbolized Rns. 5623 Downloaded by guest on September 29, 2021 5624 Genetics: Wilson et al. Proc. Natl. Acad. Sci. USA 75 (1978) friend, University of Wisconsin. Antisera to mouse submaxillary creasingly powerful tools for linkage testing. To map a newly gland renin and epidermal growth factor were the gift of T. discovered polymorphism it is necessary only to type the Inagami and S. Cohen, Vanderbilt University. Angiotensinogen recombinant inbred strains for that locus; the strain distribution was prepared from hog serum by the method of Green (18) pattern thus obtained is compared with previously defined followed by chromatography on a preparative Sephadex G-150 patterns to evaluate linkage relationships (19, 21). In addition column or was purchased from Miles Laboratories. to detecting linkage, in favorable cases it is also possible to infer the correct gene order and to estimate map distances (13- 15). RESULTS Fifty-one recombinant inbred strains derived from four All inbred strains of mice tested fall into two distinct classes. original crosses between high and low renin progenitor strains SWR/J, AKR/J, AU/SsJ, BDP/J, BUB/BnJ, CBA/J, DBA/1J, were available-24 BXD strains (13) derived from DBA/J DBA/2J, NZB/B1NJ, P/J, PL/J, RF/J, SJL/J, and SM/J pro- (high) and C57BL/6J (low); 19 AKXL strains (14) derived from duced immunodiffusion bands with antiserum to renin both AER/J (high) and C57L/J (low); 7 SWXL strains (15) derived before and after treatment with androgen. These strains are from SWR/J (high) and C57L/J (low); and HP/Ei (16), a single presumed to carry the Rnrs allele. C57BL/10J, A/J, BALB/cJ, recombinant inbred strain derived from AKR/J (high) and CBA/CaJ, CE/J, C3H/HeJ, C57BL/6J, C57BR/cdJ, C57L/J, C57BL/6J (low). The recombinant inbred strains could be LP/J, SEA/GnJ, and SEC/lReJ produced no detectable im- classified unambiguously as either low renin (Rnrb) or high munodiffusion bands even when extracts from androgen- renin (Rnrs) strains by testing either control or androgen-treated treated animals were examined. These strains are presumed to mice, indicating that genetic fixation had occurred in all 51 carry the Rnrb allele. strains. Segregation at the Rnr locus was concordant with Dip-i, We have employed recombinant inbred strains (19) derived a gene that determines electrophoretic variation in the enzyme from crosses between high and low renin inbred strains to locate dipeptidase-1 (22, 23), in 50 of the 51 recombinant inbred the Rnr locus on the mouse linkage map (20). Recombinant strains (Table 1), indicating close linkage (P < 0.001). The inbred strains are derived by continuous inbreeding from the Dip-la allele is found in C57BL/6J and C57L/J, and Dip-lb F2 generation of a cross between two unlike highly inbred is found in AKR/J, SWR/J, and DBA/2J (14, 24). The single progenitor strains. Unlinked pairs of genes reassort indepen- instance of recombination between Rnr and Dip-i is found in dently in the F2 generation. Therefore each recombinant inbred the HP/Ei strain, which is fixed for the Rnrb allele from strain is equally likely to become fixed for parental or recom- C57BL/6J and the Dip-lb allele from AKR/J. The Dip-l locus binant genotypes. Linked pairs of genes tend to be transmitted is on chromosome 1 in the mouse.
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