Research Projects

Two main project area in the lab are: Development and Regeneration

  • Congenital ocular malformations such as microphthalmia, anophthalmia and coloboma (MAC) are prevalent in ~1 in 3-4,000 individuals and are the cause for over 25% of childhood blindness worldwide. The etiology of MAC in humans is complex and can result from disruption of several factors. Coloboma, failure of optic fissure closure, alone may account up to 10% of childhood blindness. Therefore, it is vitally important to understand the molecular mechanisms underlying ocular development. While several causative genes are identified, more effort is required to define the downstream targets and events underlying eye morphogenesis.

    During normal development, eye morphogenesis initiates with evagination of bilateral optic vesicles. Subsequent invagination of the optic vesicle results in formation of the optic cup, which differentiates into retina and retinal pigment epithelium (RPE). The ventral optic cup and stalk invaginate resulting in formation of a transient gap, the optic fissure, that needs to close and fuse. Several genes have been identified as instrumental, but the precise mechanisms underlying the fusion events remain poorly understood. During all these processes, neuroepithelial cells undergo significant changes in cell shape that require tissue-tissue interaction, dynamic regulation of actin cytoskeleton, apicobasal polarity, and cell adhesion.

    We are investigating the function of Wnt and Hippo pathways and the role of the small Rho GTPase Cdc42 in mouse. We use temporally controlled and tissue-specific inactivation, RNAseq and culture approaches to determine the cellular function of pathway genes regulating evagination and regionalization of the optic vesicle, optic cup formation and closure of the optic fissure.

  • In the mature eye, the retinal pigment epithelium (RPE) is an essential epithelium interposed between the neural retina and the choroid. The RPE maintains tissue homeostasis through long-term survival, with little evidence of de novo cell production. Due to continued growth of the eye and aging, cell density decreases and RPE cells generally undergo hypertrophy. Degeneration of the central RPE causes the progressive chronic disease age-related macular degeneration (AMD), the leading cause of irreversible vision loss in the elderly population. Besides some protective strategies, no effective cure for AMD is currently available.

    Recent studies revealed that substantial cell heterogeneity may be a feature that exists throughout the RPE and, importantly, certain subsets of this heterogeneous RPE cell population may contain distinct properties contributing to regeneration. This indicates that some adult RPE cell populations retain an intrinsic capacity to renew themselves. We and others discovered in developmental studies signaling pathways critical for RPE growth and differentiation. Regeneration oftentimes re-utilizes signaling pathways that regulate a developmental program in different systems. We are currently testing several candidate signaling pathways to initiate an intrinsic regenerative response in the RPE upon injury. Our goal is to identify novel regulators stimulating de novo production of cells in the mature RPE. Identifying candidate targets for clinical therapy is critical step forward for RPE-related diseases with currently very limited therapeutic potential, such as atrophic AMD.