dab2 is required for the scavenging function of lymphatic endothelial cells in the zebrafish meninges.

To date it is only partially understood how the brain is cleared of waste products resulting from its high metabolic activity, although this process has important implications for the development and progression of neurodegenerative diseases. Lymphatic vessels play a central role in maintaining fluid and tissue homeostasis, and the recent description of meningeal lymphatic vessels within the dura mater of mice, human and zebrafish has raised considerable interest in unraveling the function of these vessels. In zebrafish, brain lymphatic endothelial cells (BLECs) constitute an additional meningeal lymphatic endothelial cell population. These highly endocytically active cells contribute to the clearance of the brain, but the molecular basis of this scavenging activity is only poorly understood. Here, we report on the characterization of zebrafish disabled 2 (dab2) mutants. Embryos lacking maternally provided dab2 show defective venous sprouting from the caudal vein plexus at 26hpf. Furthermore, we show that the cargo-specific adaptor protein is specifically expressed in BLECs, and that BLECs are significantly impeded in their capacity to internalize specific substrates injected into the cerebrospinal fluid upon loss of zygotic dab2. Our work therefore identifies Dab2 as an important member of the molecular machinery mediating the scavenging function of BLECs in the meninges.