The orphan G protein-coupled receptor, Gpr161, encodes the vacuolated lens locus and controls neurulation and lens development.
The vacuolated lens (vl) 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 vl indicates these phenotypes result from a deletion mutation in an uncharacterized orphan G protein-coupled receptor (GPCR), Gpr161. Gpr161 displays restricted expression to the lateral neural folds, developing lens, retina, limb, and CNS. Characterization of the vl 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 vl cataract or NTD phenotypes. Bioinformatic, sequence, genetic, and functional data have determined that Foxe3, a key regulator of lens development, is a gene responsible for the vl cataract-modifying phenotype. These studies have extended our understanding of the vl locus in three significant ways. One, the cloning of the vl 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 vl as a mouse model for studying the multigenic basis of NTDs and cataracts. Three, we have identified Foxe3 as a genetic modifier that interacts with Gpr161 to regulate lens development.
Matteson
Paul G
PG
Center for Advanced Biotechnology and Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
Desai
Jigar
J
Korstanje
Ron
R
Lazar
Gloria
G
Borsuk
Tanya E
TE
Rollins
Jarod
J
Kadambi
Sindhuja
S
Joseph
Jamie
J
Rahman
Taslima
T
Wink
Jason
J
Benayed
Rym
R
Paigen
Beverly
B
Millonig
James H
JH
D000818:Animals; D015153:Blotting, Western; D002386:Cataract / Q000151:congenital / Q000235:genetics; D002460:Cell Line; D003001:Cloning, Molecular; D004705:Endocytosis / Q000502:physiology; D020224:Expressed Sequence Tags; D006801:Humans; D007150:Immunohistochemistry; D007908:Lens, Crystalline / Q000254:growth & development*; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009154:Mutation; D009420:Nervous System / Q000254:growth & development*; D009436:Neural Tube Defects / Q000235:genetics; D040641:Quantitative Trait Loci; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000502:physiology*
D043562:Receptors, G-Protein-Coupled