Deletion of G protein-coupled receptor 48 leads to ocular anterior segment dysgenesis (ASD) through down-regulation of Pitx2

doi:10.1073/pnas.0708257105

Deletion of G protein-coupled receptor 48 leads to ocular anterior segment dysgenesis (ASD) through down-regulation of Pitx2

*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;
^†Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China; and
^‡School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical College; Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health P.R. China and Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry, 270 Xueyuan Road, Wenzhou, Zhejiang 325003, China

Edited by Melvin I. Simon, California Institute of Technology, Pasadena, CA, and approved February 11, 2008 (received for review August 31, 2007)

Abstract

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.

Footnotes

^§To whom correspondence should be addressed. E-mail: mliu{at}ibt.tamhsc.edu
Author contributions: J. Weng and M.L. designed research; J. Weng, J.L., X.C., C.J., X.Z., D.A., D.L., and J. Wang performed research; J.Q., L.T., J.F.M., and B.A.A. contributed new reagents/analytic tools; J. Weng and M.L. analyzed data; and J. Weng and M.L. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0708257105/DCSupplemental.