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      Leucine-Rich Repeat-Containing G Protein-Coupled Receptor-4 (LGR4, Gpr48) Is Essential for Renal Development in Mice

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          Abstract

          Leucine-rich repeat-containing G protein-coupled receptor (LGR)-4 is a G protein-coupled receptor (GPCR) with a seven-transmembrane domain structure. LGRs are evolutionally and structurally phylogenetic, classified into three subgroups and are members of the so-called orphan receptors whose ligands have yet to be identified. We generated knockout mice lacking Lgr4 (Gpr48) by targeted deletion of part of exon 18, which codes for the transmembrane and signal-transducing domains of the receptor. Lgr4 null mice were born at much less than the 25% expected frequency from crosses of Lgr4 heterozygous mice (Lgr4<sup>+/–</sup> ). Lgr4 null mice that survived in utero died shortly after birth in almost all cases. We observed striking renal hypoplasia in the null mice, accompanied by elevated concentration of plasma creatinine. Histological analysis of the P0 null mouse kidney showed a notable decrease in the total number and density of the glomerulus. Thus, the function of Lgr4 is essential to regulate renal development in the mouse. This study suggests that the Lgr4 gene is a new and important member of LGRs involved in a group of genes responsible for hereditary disease in the kidney.

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          Most cited references 17

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          Activation of orphan receptors by the hormone relaxin.

          Relaxin is a hormone important for the growth and remodeling of reproductive and other tissues during pregnancy. Although binding sites for relaxin are widely distributed, the nature of its receptor has been elusive. Here, we demonstrate that two orphan heterotrimeric guanine nucleotide binding protein (G protein)-coupled receptors, LGR7 and LGR8, are capable of mediating the action of relaxin through an adenosine 3',5'-monophosphate (cAMP)-dependent pathway distinct from that of the structurally related insulin and insulin-like growth factor family ligand. Treatment of antepartum mice with the soluble ligand-binding region of LGR7 caused parturition delay. The wide and divergent distribution of the two relaxin receptors implicates their roles in reproductive, brain, renal, cardiovascular, and other functions.
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            A transgenic mouse line that retains Cre recombinase activity in mature oocytes irrespective of the cre transgene transmission.

             K Sakai,  J. Miyazaki (1997)
            The Cre/loxP site-specific recombination system derived from bacteriophage P1 provides a convenient tool for directed modifications of genomes in various organisms. To exploit Cre-mediated manipulation of mouse genomic sequences at the zygote stage, we have developed a transgenic mouse line carrying the CAG-cre transgene in which the cre gene is under control of the cytomegalovirus immediate early enhancer-chicken beta-actin hybrid (CAG) promoter. The activity of the Cre recombinase at early stages of development was examined by crossing the CAG-cre transgenic mice to another transgenic mouse line carrying a reporter gene construct, CAG-CAT-Z, which directs expression of the E. coli lacZ gene upon Cre-mediated excision of the loxP-flanked chloramphenicol acetyltransferase (CAT) gene located between the CAG promoter and the lacZ gene. PCR-based analysis of F1 progeny from CAG-cre males x CAG-CAT-Z females showed that transmission of the CAG-cre transgene was accompanied by the complete deletion of the CAT gene of the CAG-CAT-Z transgene in all tissues, and that this deletion was never observed in the progeny without transmission of the CAG-cre gene. On the other hand, analysis of F1 mice from CAG-CAT-Z males x CAG-cre females showed that the CAG-CAT-Z transgene had undergone complete deletion of the CAT gene in all tissues irrespective of the cotransmission of the CAG-cre gene. This Cre-mediated recombination in F1 mice occurred before the two-cell stage of embryonic development, as shown by X-gal staining. The results suggest that the CAG-cre transgene is expressed in developing oocytes of CAG-cre transgenic mice, and Cre mRNA and/or protein are retained in mature oocytes irrespective of the transmission of the CAG-cre transgene, resulting in efficient Cre-mediated recombination of paternally derived target genes upon fertilization. The CAG-cre transgenic mouse should serve as a useful tool to introduce prescribed genetic modifications into the mouse embryo at the zygote stage.
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              Alpha-inhibin is a tumour-suppressor gene with gonadal specificity in mice.

              The inhibins are alpha:beta heterodimeric growth factors that are members of the transforming growth factor-beta family. To understand the physiological roles of the inhibins in mammalian development and reproduction, a targeted deletion of the alpha-inhibin gene was generated by homologous recombination in mouse embryonic stem cells. Mice homozygous for the null allele (inhibin-deficient) initially develop normally but every mouse ultimately develops mixed or incompletely differentiated gonadal stromal tumours either unilaterally or bilaterally. Inhibin is thus a critical negative regulator of gonadal stromal cell proliferation and the first secreted protein identified to have tumour-suppressor activity.
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                Author and article information

                Journal
                NEE
                Nephron Exp Nephrol
                10.1159/issn.1660-2129
                Cardiorenal Medicine
                S. Karger AG
                1660-2129
                2006
                September 2006
                21 June 2006
                : 104
                : 2
                : e63-e75
                Affiliations
                aLaboratory of Molecular Biology, Graduate School of Agricultural Science, Tohoku University, Sendai, bDivision of Molecular Medicine, Center for Translational and Advanced Animal Research, Tohoku University School of Medicine, Sendai, and cNational Research Institute for Child Health and Development, Tokyo, Japan
                Article
                93999 Nephron Exp Nephrol 2006;104:e63–e75
                10.1159/000093999
                16785743
                © 2006 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 8, Tables: 3, References: 25, Pages: 1
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/93999
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