Deletion of G protein-coupled receptor 48 leads to ocular anterior segment dysgenesis (ASD) through down-regulation of Pitx2.
The development of the anterior segment of the mammalian eye is critical for normal ocular function, whereas abnormal development can cause glaucoma, a leading cause of blindness in the world. We report that orphan G protein-coupled receptor 48 (Gpr48/LGR4) plays an important role in the development of the anterior segment structure. Disruption of Gpr48 causes a wide spectrum of anterior segment dysgenesis (ASD), including microphthalmia, iris hypoplasia, irdiocorneal angle malformation, cornea dysgenesis, and cataract. Detailed analyses reveal that defective iris myogenesis and ocular extracellular matrix homeostasis are detected at early postnatal stages of eye development, whereas ganglion cell loss, inner nuclear layer thinness, and early onset of glaucoma were detected in 6-month-old Gpr48(-/-) mice. To determine the molecular mechanism of ASD caused by the deletion of Gpr48, we performed gene expression analyses and revealed dramatic down-regulation of Pitx2 in homozygous knockout mice. In vitro studies with the constitutively active Gpr48 mutant receptor demonstrate that Pitx2 is a direct target of the Gpr48-mediated cAMP-CREB signaling pathway in regulating anterior segment development, suggesting a role of Gpr48 as a potential therapeutic target of ASD.
Weng
Jinsheng
J
Institute of Biosciences and Technology and Department of Molecular and Cellular Medicine, Texas A&M University System Health Science Center, 2121 West Holcombe Boulevard, Houston, TX 77030, USA.
Luo
Jian
J
Cheng
Xuhong
X
Jin
Chang
C
Zhou
Xiangtian
X
Qu
Jia
J
Tu
Lili
L
Ai
Di
D
Li
Dali
D
Wang
Jun
J
Martin
James F
JF
Amendt
Brad A
BA
Liu
Mingyao
M
D000818:Animals; D000869:Anterior Eye Segment / Q000002:abnormalities* / Q000254:growth & development; D002386:Cataract / Q000235:genetics; D003315:Cornea / Q000002:abnormalities / Q000254:growth & development; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000378:metabolism; D015536:Down-Regulation; D005124:Eye Abnormalities / Q000235:genetics*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005901:Glaucoma / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics*; D007498:Iris / Q000002:abnormalities / Q000254:growth & development; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism; D017384:Sequence Deletion; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics*; D000097577:Homeobox Protein PITX2
D017362:Cyclic AMP Response Element-Binding Protein; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D018398:Homeodomain Proteins; D043562:Receptors, G-Protein-Coupled; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2; C492004:Creb1 protein, mouse; C496200:LGR4 protein, mouse