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Submitted on March 31, 2004
Accepted on May 28, 2004
Division of Reproductive Biology Department of Obstetrics and Gynecology (S.M., S.S., C.K., J.V.Z, K.K., A.J.W.H.), Department of Comparative Medicine (D.M.B.), and Biology (L.V.G, H.R., M.T-L.) Stanford University, Stanford, CA 94305
* To whom correspondence should be addressed. E-mail: aaron.hsueh{at}stanford.edu.
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 
-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 two days. 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 demonstrated the widespread expression of LGR4, 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 underlies the importance of the LGR4 signaling system for the survival and growth of animals during the perinatal stage.
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