Leucine-rich repeat-containing, G protein-coupled receptor 4 null mice exhibit intrauterine growth retardation associated with embryonic and perinatal lethality
Leucine-rich repeat-containing, G protein-coupled receptor 4 null mice exhibit intrauterine growth retardation associated with embryonic and perinatal lethality
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DOI：
10.1210/me.2004-0133
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发表时间：
2004-09-01
影响因子：
--
通讯作者：
Hsueh, AJW
中科院分区：
文献类型：
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作者：
Mazerbourg, S;Bouley, DM;Hsueh, AJW
富含亮氨酸重复序列的G蛋白偶联受体（LGR）属于哺乳动物最大的蛋白质超家族，具有七个跨膜结构域。LGR根据其独特的结构域排列可以分为三个亚组。虽然已经发现两个亚组分别是糖蛋白激素和松弛素相关配体的受体，但由LGR 4 -6组成的第三LGR亚组是具有未知生理作用的孤儿受体。为了阐明该LGR亚组的功能，使用分泌陷阱方法产生LGR 4缺失小鼠，以在外显子1后立即插入β-半乳糖苷酶报告基因后删除大部分LGR 4基因。基于内源性LGR 4启动子驱动的转基因的组织化学染色分析表达LGR 4的组织。LGR 4在肾脏、肾上腺、胃、肠、心脏、骨/软骨和其他组织中广泛表达。通过野生型动物的免疫组织化学研究进一步证实了LGR 4在这些组织中的表达。对250只新生动物的生存能力的分析表明了一种倾斜的遗传模式，表明只有40%的预期LGR 4缺失小鼠出生。出生时存活的LGR 4基因敲除小鼠大多数在2 d内死亡。此外，LGR 4缺失小鼠显示宫内生长迟缓，如出生时体重下降14%以及肾脏和肝脏重量分别下降30%和40%所反映的。目前的研究结果表明LGR 4的广泛表达，以及LGR 4对胚胎生长以及肾脏和肝脏发育的重要作用。所观察到的LGR 4缺失小鼠的出生前和出生后致死率说明了LGR 4信号传导系统对于围产期动物的存活和生长的重要性。
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.