The orphan G protein-coupled receptor, <i>Gpr161</i> , encodes the <i>vacuolated lens</i> locus and controls neurulation and lens development

<jats:p> The <jats:italic>vacuolated lens</jats:italic> ( <jats:italic>vl</jats:italic> ) mouse mutant causes congenital cataracts and neural tube defects (NTDs), with the NTDs being caused by abnormal neural fold apposition and fusion. Our positional cloning of <jats:italic>vl</jats:italic> indicates these phenotypes result from a deletion mutation in an uncharacterized orphan G protein-coupled receptor (GPCR), <jats:italic>Gpr161. Gpr161</jats:italic> displays restricted expression to the lateral neural folds, developing lens, retina, limb, and CNS. Characterization of the <jats:italic>vl</jats:italic> mutation indicates that C-terminal tail of Gpr161 is truncated, leading to multiple effects on the protein, including reduced receptor-mediated endocytosis. We have also mapped three modifier quantitative trait loci (QTL) that affect the incidence of either the <jats:italic>vl</jats:italic> cataract or NTD phenotypes. Bioinformatic, sequence, genetic, and functional data have determined that <jats:italic>Foxe3</jats:italic> , a key regulator of lens development, is a gene responsible for the <jats:italic>vl</jats:italic> cataract-modifying phenotype. These studies have extended our understanding of the <jats:italic>vl</jats:italic> locus in three significant ways. One, the cloning of the <jats:italic>vl</jats:italic> locus has identified a previously uncharacterized GPCR-ligand pathway necessary for neural fold fusion and lens development, providing insight into the molecular regulation of these developmental processes. Two, our QTL analysis has established <jats:italic>vl</jats:italic> as a mouse model for studying the multigenic basis of NTDs and cataracts. Three, we have identified <jats:italic>Foxe3</jats:italic> as a genetic modifier that interacts with Gpr161 to regulate lens development. </jats:p>