Control of Cell-Cell interactions in Forebrain Morphogenesis.

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In human, between 2 and 3% of babies are born with birth defects; half of these suffering of mild to severe brain and/or eye impairments. In 40% of these, brain defect is accompanied by changes in brain and/or eye size. Understanding the source of these severe brain and eye conditions in new-born is a pre-requisite to plan therapeutic avenues. We found that mistakes in the very early separation between telencephalon (forming the future brain hemispheres) and eye, leads to abnormalities in brain and eye size in the animal model used in our lab (the zebrafish). This finding open the possibility that some of the pathologies related to microcephaly (smaller brain) or macrocephaly (bigger brain) may originate from early segregation defects. We very recently identified four key players in the process of separation between telencephalon and eye but have very little knowledge of how they act and how they connect to each other. In this proposal our goals are to:- Understand the exact nature of events required for correct separation of telencephalon and eye in fish and mouse.- Characterize the extent of brain and eye abnormalities induced by impaired brain/eye separation- Identify the conserved molecular interactions that are orchestrating the separation process. In completion of this programme of research, we will have identified the conserved cellular events driving normal formation of telencephalon and eye in vertebrates and established a model of functional molecular network controlling this process. We will also have linked our finding to human genetics and associated genes of the network to specific human brain malformations, strengthening the potential relation between tissue segregation defect and human developmental brain disorders.