The lymphatic vasculature is crucial for fluid homeostasis and immune function, and has a central role in many pathological conditions. The molecular mechanisms underlying lymphangiogenesis are poorly understood. Recently, CCBE1 has been identified in the host lab as a key regulator of lymphangiogenesis in zebrafish, mice and human. Importantly, CCBE1 has been associated to Hennekam Syndrome where patients suffer from lymphedema, cardiovascular anomalies and mental retardation.This proposal aims at elucidating the biological role of CCBE1 both on a mechanistic level, but also in biological contexts other than the lymphatic system. To that end, inducible knock out alleles of the mouse Ccbe1 gene have been generated and will be employed in the study, complemented by work in zebrafish embryos. As Hennekam Syndrome patiens suffer from mental retardation, and since Ccbe1 is expressed in the murine cortex, I will analyze neurogenesis in Ccbe1 knock-out mice. In addition to the systemic knock-out of Ccbe1, I will also induce neuron-specific deletion of Ccbe1 by different means. Second, in mutant ccbe1 zebrafish, venous sprouting is severely affected. Recent data show that in Ccbe1 mutant mice there is no ingression of veins into the hindbrain at embryonic day E10.5. Hence, I will analyze this very specific and locally restricted defect, and will also analyze the development of the venous vasculature of the hindbrain of zebrafish. Additionally, I will analyze the role of CCBE1 for venous sprouting in the skin, the retina and the liver of Ccbe1 knock-out mice. Third, mutant knock-in mouse lines will be established that express mutant or epitope-tagged wild type CCBE1 molecules to further characterize the function and distribution of CCBE1 in vivo. In summary, my work will contribute to a better understanding of the molecular function of Ccbe1 in lymphangiogenesis and will provide vital insight into the requirement for Ccbe1 on other aspects of organogenesis.
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