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

Paul G. Matteson, Jigar Desai, Ron Korstanje, Gloria Lazar, Tanya E. Borsuk, Jarod Rollins, Sindhuja Kadambi, Jamie Joseph, Taslima Rahman, Jason Wink, Rym Benayed, Beverly Paigen, James Millonig

Research output: Contribution to journalArticle

42 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2088-2093
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number6
DOIs
StatePublished - Feb 12 2008

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Neurulation
Internal-External Control
G-Protein-Coupled Receptors
Lenses
Neural Tube Defects
Cataract
Neural Crest
Quantitative Trait Loci
Phenotype
Organism Cloning
Sequence Deletion
Endocytosis
Computational Biology
Retina
Tail

All Science Journal Classification (ASJC) codes

  • General

Keywords

  • Cataracts
  • Foxe3
  • Spina bifida

Cite this

Matteson, Paul G. ; Desai, Jigar ; Korstanje, Ron ; Lazar, Gloria ; Borsuk, Tanya E. ; Rollins, Jarod ; Kadambi, Sindhuja ; Joseph, Jamie ; Rahman, Taslima ; Wink, Jason ; Benayed, Rym ; Paigen, Beverly ; Millonig, James. / The orphan G protein-coupled receptor, Gpr161, encodes the vacuolated lens locus and controls neurulation and lens development. In: Proceedings of the National Academy of Sciences of the United States of America. 2008 ; Vol. 105, No. 6. pp. 2088-2093.
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Matteson, PG, Desai, J, Korstanje, R, Lazar, G, Borsuk, TE, Rollins, J, Kadambi, S, Joseph, J, Rahman, T, Wink, J, Benayed, R, Paigen, B & Millonig, J 2008, 'The orphan G protein-coupled receptor, Gpr161, encodes the vacuolated lens locus and controls neurulation and lens development', Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 6, pp. 2088-2093. https://doi.org/10.1073/pnas.0705657105

The orphan G protein-coupled receptor, Gpr161, encodes the vacuolated lens locus and controls neurulation and lens development. / Matteson, Paul G.; Desai, Jigar; Korstanje, Ron; Lazar, Gloria; Borsuk, Tanya E.; Rollins, Jarod; Kadambi, Sindhuja; Joseph, Jamie; Rahman, Taslima; Wink, Jason; Benayed, Rym; Paigen, Beverly; Millonig, James.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 6, 12.02.2008, p. 2088-2093.

Research output: Contribution to journalArticle

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T1 - The orphan G protein-coupled receptor, Gpr161, encodes the vacuolated lens locus and controls neurulation and lens development

AU - Matteson, Paul G.

AU - Desai, Jigar

AU - Korstanje, Ron

AU - Lazar, Gloria

AU - Borsuk, Tanya E.

AU - Rollins, Jarod

AU - Kadambi, Sindhuja

AU - Joseph, Jamie

AU - Rahman, Taslima

AU - Wink, Jason

AU - Benayed, Rym

AU - Paigen, Beverly

AU - Millonig, James

PY - 2008/2/12

Y1 - 2008/2/12

N2 - 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.

AB - 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.

KW - Cataracts

KW - Foxe3

KW - Spina bifida

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