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

doi:10.1073/pnas.0705657105

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

*Center for Advanced Biotechnology and Medicine,
^§Department of Neuroscience and Cell Biology, University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School, Piscataway, NJ 08854;
^‡The Jackson Laboratory, Bar Harbor, ME 04609; and
^¶Department of Genetics, Rutgers University, Piscataway, NJ 08854

Edited by Kathryn V. Anderson, Sloan-Kettering Institute, New York, NY, and approved December 18, 2007 (received for review June 16, 2007)

Abstract

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.

Footnotes

^‖To whom correspondence should be sent. E-mail: millonig{at}cabm.rutgers.edu
Author contributions: P.G.M., J.D., and R.K. contributed equally to this work; P.G.M., J.D., R.K., J.R., B.P., and J.H.M. designed research; P.G.M., J.D., R.K., G.L., T.E.B., S.K., J.J., J.W., and R.B. performed research; T.R. contributed new reagents/analytic tools; P.G.M., J.D., R.K., G.L., T.E.B., S.K., J.W., R.B., and J.H.M. analyzed data; and P.G.M., J.D., R.K., and J.H.M. wrote the paper.
↵ ^†Present address: Harvard Medical School and The Children's Hospital, 300 Longwood Avenue, Boston, MA 02115.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The sequence reported in this paper has been deposited in the Genbank database (accession no. EF197953).
This article contains supporting information online at www.pnas.org/cgi/content/full/0705657105/DC1.
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