Neonatal Lethality of LGR5 Null Mice Is Associated with Ankyloglossia and Gastrointestinal Distension

Abstract

The physiological role of an orphan G protein-coupled receptor, LGR5, was investigated by targeted deletion of this seven-transmembrane protein containing a large N-terminal extracellular domain with leucine-rich repeats.LGR5 null mice exhibited 100% neonatal lethality characterized by gastrointestinal tract dilation with air and an absence of milk in the stomach. Gross and histological examination revealed fusion of the tongue to the floor of oral cavity in the mutant newborns and immunostaining of LGR5 expression in the epithelium of the tongue and in the mandible of the wild-type embryos. The observed ankyloglossia phenotype provides a model for understanding the genetic basis of this craniofacial defect in humans and an opportunity to elucidate the physiological role of the LGR5 signaling system during embryonic development.The leucine-rich repeat-containing, G protein-coupled receptors (LGRs) designated LGR4 through LGR8 are structurally similar to receptors for gonadotropins and thyrotropin (11,12). These receptors are characterized by a large N-terminal extracellular domain containing leucine-rich repeats followed by a seven-transmembrane region. Phylogenetic analyses showed three LGR subgroups: the glycoprotein hormone receptors; the subgroup of LGR4, LGR5, and LGR6; and a third subgroup represented by LGR7 and LGR8 recently found to be receptors for the relaxin family ligands (13,15,23). Evolutionary analyses suggested that these three subgroups of LGRs existed before the divergence of vertebrates and invertebrates (10). LGR5, also known as GPR49, HG38, or FEX, is a large protein consisting of 18 extracellular leucine-rich repeats together with a seven-transmembrane region (8,12,17). UnlikeLGRs in the other two subgroups, the ligands and physiological functions for the LGR4, LGR5, and LGR6 genes are unclear.Ankyloglossia is a rare human craniofacial defect associated with difficulties in an infant's ability to breast-feed and defective speech articulation (6,16,18). In patients with this disorder, the lingual frenulum, which attaches the tongue to the floor of the oral cavity, extends to the tip of the tongue, thereby preventing optimal tongue movement. Limitation of tongue movement may vary from very mild to complete fusion of the tongue to the floor of the mouth. Ankyloglossia in breastfeeding infants can cause ineffective latch, inadequate milk transfer, and maternal nipple pain, resulting in slower weight gain and untimely weaning. Some cases of ankyloglossia are associated with cleft palate (CPX; MIM 303400; OMIM database, Johns Hopkins University, Baltimore, Md.) and are inherited as an X-linked disorder caused by mutations in TBX22, a T-box transcription factor gene located in Xq21 (3).In an attempt to elucidate the physiological roles of the subgroup of orphan LGRs consisting of LGR4, LGR5, and LGR6, we performed gene deletion experiments with LGR5 using a mouse model. Here, we report that the LGR5 null mice exhibit neonatal lethality associated with ankyloglossia characterized by fusion of the ...

Nasal speech and hypothyroidism are common hallmarks of 12q15 microdeletions

“…21,22 The LGR5 knockout mouse model is associated with neonatal lethality, gastrointestinal distention and ankyloglossia. 23 Although all three patients present with nasal speech, none of the genes in the SRO have a clear function in palate formation.…”

Leucine-Rich Repeat-Containing G-Protein Coupled Receptor 5/GPR49 Activates G12/13-Rho GTPase Pathway

“…LGR5 and LGR6 have attracted much attention from the stem cell community as a result of their specific expression in proliferating adult stem cells in various tissues, including hair follicles, intestines, stomach, and skin, whereas LGR4 shows a broader expression pattern that extends beyond stem cells (Barker and Clevers, 2010;Van Schoore et al, 2005). Furthermore, LGR4 and LGR5 null mice show neonatal lethality, whereas LGR6 knockout mice are healthy and fertile Morita et al, 2004;Snippert et al, 2010). These observations led us to investigate whether LGR4 and LGR6 regulate SRF-RE reporter activity.…”

Dynamic Expression of Lgr5, a Wnt Target Gene, in the Developing and Mature Mouse Cochlea

“…008875; Bar Harbor, ME). Homozygous Lgr5-deficient mice die perinatally (Morita et al 2004). Knock-in of the gene encoding enhanced green fluorescent protein (EGFP) into the first exon of Lgr5 results in the expression of EGFP that faithfully represents Lgr5 expression in the heterozygotes with no reported phenotypes (Barker et al 2007).…”