Judith West-Mays

, PhD

Professor, Pathology and Molecular Medicine

Division: Anatomy

McMaster University
1R10 Health Sciences Centre
905-521-2100 ext. 26237
westmayj@mcmaster.ca

Currently accepting Graduate Students
Currently accepting Post Doctoral Fellows

Education and Professional Standing

• PhD Vision Science/Biology, University of Waterloo, 1993
• MSc Physiological Optics/Biology, University of Waterloo, 1990
• HBSc Biology, Wilfrid Laurier University, 1988

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Interests

Molecular and Genetic Mechanisms Regulating Eye Development and Disease

Although the loss of vision is not typically life threatening, in the developing world a person's life expectancy after going blind is only two years. In addition, blindness significantly impacts an individual's quality of life and outside of mental incapacity, blindness is the disability people fear most. Blindness can be the result of the progression of an age-related disease. However, congenital syndromes or disorders due to genetic defects and/or environmental conditions can also be responsible for the lack of function of the visual system at birth. It is now suspected that gene mutations may also be responsible for ocular diseases that present later in life, such as glaucoma and Age-related Macular Degeneration (AMD). The general objective of my research program is to identify the genes and molecular mechanisms involved in development and differentiation of the eye, and further determine how these mechanisms may be perturbed in blinding ocular disease.

My research focuses on two central themes related to ocular disorders:

Role of candidate disease genes (transcription factor AP-2) in development and differentiation of the eye and in congenital ocular disorders

Although eye and lens development have been classic models used to demonstrate concepts of inductive interactions in development, the identity and specific roles of multiple regulatory molecules controlling ocular morphogenesis remain unknown. Our long-term goal is to define the cascade of interacting genes responsible for eye formation in order to reveal candidate disease genes involved in congenital anomalies in the anterior segment of the eye including cataracts, glaucoma and corneal dystrophies.

My laboratory has identified a family of genes, known as AP-2 (Activating Protein-2) transcription factors, as candidate regulators for controlling early eye and lens development. The AP-2 factors are a family of retinoic acid-responsive genes, which have been conserved throughout evolution, and unlike more ubiquitous transcription factors, AP-2 is a cell type-specific transcription factor, expressed in surface ectoderm, brain, and neural crest cells and their derivatives. My lab has shown that the three AP-2 genes, a, b and g have distinct and overlapping expression patterns in the developing eye. We have further shown that mice lacking the AP-2alpha gene (Knockout mice) exhibit severe ocular defects including a mutant lens which fails to separate from the overlying ectoderm (Dev. Biol.206:46-62, 1999). This defect is correlated with the misexpression of two genes involved in lens development and differentiation, Pax6 and MIP26. We have also shown that ectopic expression of AP-2a in the lens of transgenic mice (aA-AP-2alpha) resulted in an inhibition of fiber cell elongation and migration and in fiber cell denucleation (Dev. Biol 71: 206-216, 2003). The defects were correlated with expanded cadherin expression and delayed MIP expression in the transitional zone. These findings were paramount in demonstrating a requirement for AP-2alpha in early eye and lens development. We have now embarked on a full-scale research program to determine where the AP-2 genes reside in the genetic cascade controlling eye and lens development.

Role of TGFbeta and Matrix Metalloproteinases in subcapsular cataract formation and ocular fibrosis

Loss of transparency of the lens, or cataract, is the leading cause of blindness in the world. The development of a preventative therapy for cataract almost certainly depends on a greater understanding of the basic molecular processes regulating growth, differentiation and maintenance of the lens. Two related forms of cataract, subcapsular cataract and secondary cataract (post-operative opacification), involve the increased proliferation and transformation of lens epithelial cells into plaques of large "spindle shaped" myofibroblasts which express the contractile filament, a-smooth muscle actin (alpha-SMA). Our hypothesis is that Matrix Metalloproteinases (MMPs) play a functional role in the transition of lens epithelial cells into mesenchymal or myofibroblast cells (EMT) during subcapsular cataract formation. Preliminary findings show that an increase in expression of gelatinase A (MMP-2) accompanies the EMT induced in a rat cataract model. This may reflect a downstream involvement of MMPs in cataractogenesis, secondary to the initial cause. However, it is equally probable that MMPs play a more active role in initiating the events leading up to cataract formation. For example, MMPs have been shown to directly influence the EMT of many cell types and to activate latent TGFbeta. Our proposed studies will distinguish between these two alternate hypotheses (direct or indirect roles). If MMPs participate in cataractogenesis, the ability to block MMP expression and activity may be of high impact to lens and cataract research since it would provide the basis for investigation of a novel therapy for the prevention of cataracts. Treatment of the rat lens (whole lens and explants) with the cytokine TGFbeta has become an excellent in vitro model for inducing cataractous changes which resemble those seen in humans. However, the mouse lens is better suited for use in molecular genetic studies. We will expand the rat TGFbeta model to the mouse lens. Success with this model will enable this laboratory and others to test genes potentially involved in cataractogenesis using current null mutant and transgenic mice.

Methodologies include genetically targeted approaches in mice (transgenics, conditional mutants; null mutants), analyses of phenotypes using molecular and immunohistochemical approaches and cell culture models and proteomic and genomic approaches to further define the genetic cascade controlling eye development. We predict that these studies will lead to therapeutic strategies (via vitreal implants or gene therapy approaches) for correcting or preventing vision loss.

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Team Members

Lab Technician

Paula Deschamps

Post-Doctoral Fellows

Jennifer Robertson

Graduate Students

Erin Bassett, Giuseppe Pino, Zahra Nathu, Christine Kerr, Anna Korol, Madhuja Gupta

Selected Publications

• West-Mays, J.A. & Pino, G. (2007). Matrix metalloproteinases as mediators of primary and secondary cataracts. Expert Rev Ophthalmol, 2(6), 931-938.
• Pontoriero, G.F., Smith, A.N., Miller, L.A., Radice, G.L., West-Mays, J.A., & Lang, R.A. (2009). Co-operative roles for E-cadherin and N-cadherin during lens vesicle separation and lens epithelial cell survival.  Dev Biol, 326(2), 403-417.
• Nathu, Z., Dwivedi, D.J., Reddan, J.R., Sheardown, H., Margetts, P.J., & West-Mays, J.A. (2009). Temporal changes in MMP mRNA expression in the lens epithelium during anterior subscapular cataract formation. Exp Eye Res, 88(2), 323-330.
• Pontoriero, G.F, Deschamps, P/, Ashery-Padan, R., Wong, R., Yang, Y., Zavadil, J., Cvekl, A., Sullivan, S., Williams, T., & West-Mays, J.A. (2008). Cell autonomous roles for AP-2alpha in lens vesicle separation and maintenance of the lens epithelial cell phenotype. Dev Dyn, 237(3), 602-617.
• Bassett, E.A., Pontoriero, G.F., Feng, W., Marquardt, T., Fini, M.E.,Williams, T., & West-Mays, J.A. (2007). Conditional Deletion of AP-2a in the Developing Retina Demonstrates Non-Cell Autonomous Roles for AP-2a in Optic Cup Development. Molecular Cellular Biology, 27, 7497-7510.
• Robertson, J.V., Nathu, Z., Najjar, A., Dwivedi, D., Gauldie, J., & West-Mays, J.A. (2007). Adenoviral Gene Transfer of Bioactive TGF-b1 to the Rodent Eye as a Novel Model for Anterior Subcapsular Cataract. Molecular Vision, 13, 457-469.
• Makhani, L., Williams, T., & West-Mays J.A. (2007). Genetic Analysis Indicates that Transcription Factors AP-2a and Pax6 Cooperate in Normal Patterning and Morphogenesis of the Lens. Molecular Vision, 13, 1215-1225.