Molecular mechanisms regulating optic fissure closure

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Eye development is an intricate process, ranging from the definition of the eye field, to optic vesicle evagination and differentiation of the neuroretina. After lens induction the dorsal retinal anlage extends and folds ventrally with its anterior and posterior parts. In the area where these latter parts will meet, an optic fissure is visible. During normal development, this optic fissure is only transiently present. The fissure closes by fusion of the anterior and posterior edges of the retinal parts. Defects of optic fissure closure, referred to as coloboma, can affect several eye structures like iris, choroidea or retina and may be combined with malformations of other parts of the central nervous system (CNS), and also other organs (i.e. heart and kidney). Gene mutations identified in affected patients as well as in mice have led to the proposal of a coloboma gene regulatory network. Although many genes, primarily transcription factors that lead to coloboma formation if altered have been identified, the link to effector molecules mediating the process is still elusive. From our preliminary work we know that loss of TGF-beta2 leads, in addition to numerous already described defects in eye development, to a lack of optic fissure closure and a hypercellular, disorganized retina. TGF-betas are a family of extracellular mediators regulating cell proliferation, differentiation, survival and death. The specific aim of the proposed project is to unravel the molecular and mechanistic details of how extracellular molecules such as TGF-beta orchestrate optic fissure closure and how TGF-beta dependent signaling integrates into the known coloboma gene network. The project is a joint effort of two laboratories with unique expertise in retina development in fish and mouse. The project will start by a systematic analysis of potential TGF-beta target genes using TGF-beta2 null mice in comparison to wild type litter mates at E13.5 (before optic fissure closure) and E16.5 (proliferation and differentiation of neuroretina), followed by appropriate bioinformatics processing and database analyses. Functional analysis of candidate genes will be done in fish. Furthermore, a retina-specific mouse line lacking TGF-beta signaling (Cre-Rx3 x TbR-IIflox/flox) will be generated to study TGF-beta induced retina development independent of mesenchyme-derived TGF-beta signaling.