Regulation of Eye Morphogenesis

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Project Summary Congenital ocular malformations such as microphthalmia, anophthalmia and coloboma are prevalent in 1 in 3- 4,000 individuals and are the cause for over 25% of childhood blindness worldwide. Defective closure of the optic fissure (coloboma) 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. In our previous project, we showed that Porcn signaling needs to be tightly regulated during optic cup formation and optic fissure closure. The Rho GTPase Cdc42 is critical for optic vesicle invagination and growth of the optic cup, as well for optic fissure closure. Higher resolution Airyscan imaging revealed the presence of actin-rich, filopodia-like extensions in the closing fissure. Important gaps in our understanding are how the fissure margins make contact during the closure process and how growth of optic cup domains is coordinated. The molecular, unconventional motor Myosin X (Myo10) can induce filopodia formation and is a novel candidate gene for microphthalmia in humans. Our preliminary data shows that Myo10 mutant mice can exhibit coloboma and microphthalmia. In Aim 1 of this renewal application, we propose to investigate the role of Myo10 in ocular tissues using inducible conditional inactivation. Furthermore, the Hippo signaling pathway is a novel key regulatory pathway controlling distinct processes during mammalian eye development. We discovered an early role of the upstream regulator neurofibromin 2 (Nf2) in restricting retinal pigment epithelium (RPE) proliferation in the invaginating optic cup, critical for proper optic fissure closure. In Aim 2, we propose to examine how Nf2 disruption causes extended RPE proliferation in the early optic cup. In addition, our preliminary data shows an early effect on ocular growth by modulation of Hippo signaling in ocular and periocular tissues. In Aim 3, we will analyze the precise role of Yap/Taz and Nf2 during early optic cup morphogenesis. The studies proposed here will be a critical step toward an understanding of the cellular and molecular mechanisms controlling eye morphogenesis and important for advancing treatment and regenerative efforts of ocular diseases.