Heparan sulfate deficiency leads to Peters anomaly in mice by disturbing neural crest TGF-β2 signaling

Department of Ophthalmology and Visual Science, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.
The Journal of clinical investigation (Impact Factor: 13.22). 07/2009; 119(7):1997-2008. DOI: 10.1172/JCI38519
Source: PubMed


During human embryogenesis, neural crest cells migrate to the anterior chamber of the eye and then differentiate into the inner layers of the cornea, the iridocorneal angle, and the anterior portion of the iris. When proper development does not occur, this causes iridocorneal angle dysgenesis and intraocular pressure (IOP) elevation, which ultimately results in developmental glaucoma. Here, we show that heparan sulfate (HS) deficiency in mouse neural crest cells causes anterior chamber dysgenesis, including corneal endothelium defects, corneal stroma hypoplasia, and iridocorneal angle dysgenesis. These dysfunctions are phenotypes of the human developmental glaucoma, Peters anomaly. In the neural crest cells of mice embryos, disruption of the gene encoding exostosin 1 (Ext1), which is an indispensable enzyme for HS synthesis, resulted in disturbed TGF-beta2 signaling. This led to reduced phosphorylation of Smad2 and downregulated expression of forkhead box C1 (Foxc1) and paired-like homeodomain transcription factor 2 (Pitx2), transcription factors that have been identified as the causative genes for developmental glaucoma. Furthermore, impaired interactions between HS and TGF-beta2 induced developmental glaucoma, which was manifested as an IOP elevation caused by iridocorneal angle dysgenesis. These findings suggest that HS is necessary for neural crest cells to form the anterior chamber via TGF-beta2 signaling. Disturbances of HS synthesis might therefore contribute to the pathology of developmental glaucoma.


Available from: Hidenobu Tanihara, Apr 21, 2015

Click to see the full-text of:

Article: Heparan sulfate deficiency leads to Peters anomaly in mice by disturbing neural crest TGF-β2 signaling

8.57 MB

See full-text
  • Source
    • "For instance, heterozygous BMP4 mutant mice were found to have anterior dysgenesis and elevated IOP, leading to development of congenital glaucoma (Chang et al., 2001). Genetic ablation of the gene encoding Ext1, which is involved in the biosynthesis of the heparan sulfate GAG, led to altered TGFb2 signaling and down-regulation of two transcription factors, FOXC1 and PITX2 (Iwao et al., 2009). In Ext1 À/À mice, IOP was elevated due to iridocorneal angle dysgenesis. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The trabecular meshwork (TM) is located in the anterior segment of the eye and is responsible for regulating the outflow of aqueous humor. Increased resistance to aqueous outflow causes intraocular pressure to increase, which is the primary risk factor for glaucoma. TM cells reside on a series of fenestrated beams and sheets through which the aqueous humor flows to exit the anterior chamber via Schlemm's canal. The outer trabecular cells are phagocytic and are thought to function as a pre-filter. However, most of the outflow resistance is thought to be from the extracellular matrix (ECM) of the juxtacanalicular region, the deepest portion of the TM, and from the inner wall basement membrane of Schlemm's canal. It is becoming increasingly evident that the extracellular milieu is important in maintaining the integrity of the TM. In glaucoma, not only have ultrastructural changes been observed in the ECM of the TM, and a significant number of mutations in ECM genes been noted, but the stiffness of glaucomatous TM appears to be greater than that of normal tissue. Additionally, TGFβ2 has been found to be elevated in the aqueous humor of glaucoma patients and is assumed to be involved in ECM changes deep with the juxtacanalicular region of the TM. This review summarizes the current literature on trabecular ECM as well as the development and function of the TM. Animal models and organ culture models targeting specific ECM molecules to investigate the mechanisms of glaucoma are described. Finally, the growing number of mutations that have been identified in ECM genes and genes that modulate ECM in humans with glaucoma are documented. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Experimental Eye Research 04/2015; 133. DOI:10.1016/j.exer.2014.07.014 · 2.71 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The methods and apparatuses for precise measurement of coaxial lines are considered usng the unified methodological approach and general mathematical model of the transmission parameter measurer for coaxial lines.
    Actual Problems of Electronic Instrument Engineering Proceedings, 2004. APEIE 2004. 2004 7th International Conference on; 10/2004
  • [Show abstract] [Hide abstract]
    ABSTRACT: The neural crest is a remarkable embryonic population of cells found only in vertebrates and has the potential to give rise to many different cell types contributing throughout the body. These derivatives range from the mesenchymal bone and cartilage comprising the facial skeleton, to neuronal derivatives of the peripheral sensory and autonomic nervous systems, to melanocytes throughout the body, and to smooth muscle of the great arteries of the heart. For these cells to correctly progress from an unspecifi ed, nonmigratory population to a wide array of dynamic, differentiated cell types-some of which retain stem cell characteristics presumably to replenish these derivatives-requires a complex network of molecular switches to control the gene programs giving these cells their defi ning structural, enzymatic, migratory, and signaling capacities. This review will bring together current knowledge of neural crest-specifi c transcription factors governing these progressions throughout the course of development. A more thorough understanding of the mechanisms of transcriptional control in differentiation will aid in strategies designed to push undifferentiated cells toward a particular lineage, and unraveling these processes will help toward reprogramming cells from a differentiated to a more naive state.
Show more