Congenital eye disease leading to blindness affects millions of children worldwide, and one of its major causes is abnormal lens development. Previous studies>have implicated multiple signaling molecules, including bone morphogenic proteins (BMP) and fibroblast growth factors (FGF), in early lens development. However, regulation of these morphogen during lens development is still largely unknown. As essential components of major signaling pathways, cell surface glycoproteins are known to participate in both morphogen transport and morphogen-receptor interaction. In particular, the Drosophila heparan sulfate proteoglycan biosynthetic gene, sulfateless, can modulate FGF, Dpp(BMP), Wingless(Wnt) and Hedgehog signaling. It therefore raises the question as to what extent the vertebrate homologues of sulfateless, known as NDST genes, also regulate signal transductions in the lens. Our long-term goal is to understand the regulation of morphogenic signals in the lens. In this application, we would like to test the hypothesis that the heparan sulfate proteoglycan biosynthetic gene, NDST1, controls early lens development by modulating signal transduction pathway(s).
In specific aim 1, we propose to identify the molecular defects in NDST1 mutant lens by examining the expression patterns of lens develomental genes.
In specific aim 2, we will assay the activity of lens specific signaling, including FGF and BMP pathways. Finally, we will determine in specific aim 3 the tissue specific requirement of NDST1 during eye development by analyzing conditional knockouts of NDST1. Together, these studies aim to establish the molecular basis of NDST1 function in lens, providing further insight into the function of heparan sulfate in vertebrate signaling pathways. In this project, we plan to study the mechanism of lens development by investigating the function of NDST1 gene, and we propose that NDST1 regulates signaling pathways in lens. Completion of our studies will advance the understanding of the genetic program underlying lens development, and will contribute to detection and treatment of congenital ocular diseases.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Anterior Eye Disease Study Section (AED)
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Araj, Houmam H
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Indiana University-Purdue University at Indianapolis
Schools of Medicine
United States
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Cvekl, Ales; Zhang, Xin (2017) Signaling and Gene Regulatory Networks in Mammalian Lens Development. Trends Genet 33:677-702
Balasubramanian, Revathi; Zhang, Xin (2016) Mechanisms of FGF gradient formation during embryogenesis. Semin Cell Dev Biol 53:94-100
Tao, Chenqi; Zhang, Xin (2016) Retinal Proteoglycans Act as Cellular Receptors for Basement Membrane Assembly to Control Astrocyte Migration and Angiogenesis. Cell Rep 17:1832-1844
Mathew, Grinu; Hannan, Abdul; Hertzler-Schaefer, Kristina et al. (2016) Targeting of Ras-mediated FGF signaling suppresses Pten-deficient skin tumor. Proc Natl Acad Sci U S A 113:13156-13161
Cai, Zhigang; Grobe, Kay; Zhang, Xin (2014) Role of heparan sulfate proteoglycans in optic disc and stalk morphogenesis. Dev Dyn 243:1310-6
Hertzler-Schaefer, Kristina; Mathew, Grinu; Somani, Ally-Khan et al. (2014) Pten loss induces autocrine FGF signaling to promote skin tumorigenesis. Cell Rep 6:818-26
Tao, Chenqi; Zhang, Xin (2014) Development of astrocytes in the vertebrate eye. Dev Dyn 243:1501-10
Pan, Yi; Carbe, Christian; Kupich, Sabine et al. (2014) Heparan sulfate expression in the neural crest is essential for mouse cardiogenesis. Matrix Biol 35:253-65
Li, Hongge; Tao, Chenqi; Cai, Zhigang et al. (2014) Frs2? and Shp2 signal independently of Gab to mediate FGF signaling in lens development. J Cell Sci 127:571-82
Cai, Zhigang; Tao, Chenqi; Li, Hongge et al. (2013) Deficient FGF signaling causes optic nerve dysgenesis and ocular coloboma. Development 140:2711-23

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