Genetic defects of vision are a common cause of blindness in children. Such defects include gross developmental anomalies such as anophthalmia and microphthalmia, optic nerve hypoplasia, coloboma, and inherited retinal degenerations. Microphthalmia and associated birth defects accounts for 1 to 1.9 per 10,000 live births worldwide. The socio-economic consequences and healthcare impact are obvious. Up to 80% of microphthalmic cases occur as part of over 100 genetic syndromes. These anomalies that are frequently associated with microphthalmia include coloboma, craniofacial, skeletal, renal, and cardiac defects. Nevertheless, molecular mechanisms that lead to these dire conditions are largely unknown. Recent studies in both avian and murine systems have shown that diffusible factors such as Bone morphogenetic proteins (BMPs) signal transduction pathway may be important regulatory components that regulate not only the size but also the polarity of the vertebrate eye. There are also compelling evidence showing that these signaling pathways are important in regulating the differentiation processes of retinal ganglion cells (RGCs) in the neuroretina and in maintaining the laminar structure of postnatal retinas. However, how these signaling molecules influence transcriptional events in the cell nucleus are largely unexplored. The current proposal is to establish the Msx2 gene as a key component of BMP signaling in controlling optic cup formation. The long-term goal of this project is to elucidate the molecular mechanisms underlying some pediatric ocular anomalies, such as microphthalmia, coloboma and associated ocular malformations. Developmental paradigms have always guided our quest for the understanding of disease processes. Integration of various signaling mechanisms will significantly advance our understanding of genetic control mechanisms that govern normal eye development and pathogenesis. This insight is essential for the development of new approaches to disease management and rational therapies. We believe that the analysis of the ocular malformation in the Msx2 transgenic animals will provide a plausible molecular explanation on how pediatric anomalies including microphthalmia and coloboma may arise. By targeting BMP signaling and its upstream and downstream mediators, one may find a fertile ground for detecting mutations that cause syndromic microphthalmia. ? ? ?

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-AED (01))
Program Officer
Liberman, Ellen S
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Southern California
Schools of Dentistry
Los Angeles
United States
Zip Code
Zhao, Jiangyue; Kawai, Kirio; Wang, Hongyan et al. (2012) Loss of Msx2 function down-regulates the FoxE3 expression and results in anterior segment dysgenesis resembling Peters anomaly. Am J Pathol 180:2230-9
Yue, ZhiCao; Zhuang, FengFeng; Liu, Yi-Hsin et al. (2010) Interrogating cell signalling network sensitively monitors cell fate transition during early differentiation of mouse embryonic stem cells. Sci China Life Sci 53:78-86
Bai, Shumei; Liu, Shilian; Guo, Xuxiao et al. (2009) Proteome analysis of biomarkers in the cerebrospinal fluid of neuromyelitis optica patients. Mol Vis 15:1638-48
Zhuang, Fengfeng; Nguyen, Manuel P; Shuler, Charles et al. (2009) Analysis of Msx1 and Msx2 transactivation function in the context of the heat shock 70 (Hspa1b) gene promoter. Biochem Biophys Res Commun 381:241-6
Yue, Zhicao; Zhuang, Fengfeng; Kumar, Rajar et al. (2009) Cell kinase activity assay based on surface enhanced Raman spectroscopy. Spectrochim Acta A Mol Biomol Spectrosc 73:226-30
Zhuang, Fengfeng; Yen, Philip; Zhao, Jiangyue et al. (2008) Dynamic intracellular distribution of Eaf2 and its potential involvement in UV-Induced DNA damage response. DNA Cell Biol 27:649-56
Sun, Jianping; Liu, Yi-Hsin; Chen, Hui et al. (2007) Deficient Alk3-mediated BMP signaling causes prenatal omphalocele-like defect. Biochem Biophys Res Commun 360:238-43