title: Leucine-rich repeat-containing, G protein-coupled receptor 4 null mice exhibit intrauterine growth retardation associated with embryonic and perinatal lethality.
abstract: Leucine-rich repeat-containing, G protein-coupled receptors (LGRs) belong to the largest mammalian superfamily of proteins with seven-transmembrane domains. LGRs can be divided into three subgroups based on their unique domain arrangement. Although two subgroups have been found to be receptors for glycoprotein hormones and relaxin-related ligands, respectively, the third LGR subgroup, consisting of LGR4-6, are orphan receptors with unknown physiological roles. To elucidate the functions of this subgroup of LGRs, LGR4 null mice were generated using a secretory trap approach to delete the majority of the LGR4 gene after the insertion of a beta-galactosidase reporter gene immediately after exon 1. Tissues expressing LGR4 were analyzed based on histochemical staining of the transgene driven by the endogenous LGR4 promoter. LGR4 was widely expressed in kidney, adrenal gland, stomach, intestine, heart, bone/cartilage, and other tissues. The expression of LGR4 in these tissues was further confirmed by immunohistochemical studies in wild-type animals. Analysis of the viability of 250 newborn animals suggested a skewed inheritance pattern, indicating that only 40% of the expected LGR4 null mice were born. For the LGR4 null mice viable at birth, most of them died within 2 d. Furthermore, the LGR4 null mice showed intrauterine growth retardation as reflected by a 14% decrease in body weight at birth, together with 30% and 40% decreases in kidney and liver weights, respectively. The present findings demonstrate the widespread expression of LGR4, and an essential role of LGR4 for embryonic growth, as well as kidney and liver development. The observed pre- and postnatal lethality of LGR4 null mice illustrates the importance of the LGR4 signaling system for the survival and growth of animals during the perinatal stage.
authors.affiliation: Division of Reproductive Biology, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, California 94305-5317, USA.
authors.forename: Sabine
authors.initials: S
authors.lastname: Mazerbourg
authors.forename: Donna M
authors.initials: DM
authors.lastname: Bouley
authors.forename: Satoko
authors.initials: S
authors.lastname: Sudo
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Klein
authors.forename: Jian V
authors.initials: JV
authors.lastname: Zhang
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kawamura
authors.forename: Lisa V
authors.initials: LV
authors.lastname: Goodrich
authors.forename: Helen
authors.initials: H
authors.lastname: Rayburn
authors.forename: Marc
authors.initials: M
authors.lastname: Tessier-Lavigne
authors.forename: Aaron J W
authors.initials: AJ
authors.lastname: Hsueh
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004847:Epithelial Cells / Q000276:immunology; D005260:Female; D005317:Fetal Growth Retardation / Q000209:etiology*; D015870:Gene Expression / Q000235:genetics; D005804:Genes, Lethal; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000235:genetics; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000235:genetics; D007668:Kidney / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D007930:Leucine / Q000032:analysis / Q000235:genetics*; D008099:Liver / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional / Q000235:genetics; D011247:Pregnancy; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D051381:Rats; D017526:Receptor, IGF Type 1 / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000032:analysis / Q000235:genetics* / Q000502:physiology*; D020449:Repetitive Sequences, Amino Acid; D014018:Tissue Distribution; D001616:beta-Galactosidase / Q000032:analysis / Q000235:genetics
chemical_list: D018970:Insulin-Like Growth Factor Binding Protein 1; D018971:Insulin-Like Growth Factor Binding Protein 2; C496200:LGR4 protein, mouse; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D017526:Receptor, IGF Type 1; D001616:beta-Galactosidase; D007930:Leucine