VEGF modulates NMDA receptors activity in cerebellar granule cells through Src-family kinases before synapse formation.

NMDA type glutamate receptors (NMDARs) are best known for their role in synaptogenesis and synaptic plasticity. Much less is known about their developmental role before neurons form synapses. We report here that VEGF, which promotes migration of granule cells (GCs) during postnatal cerebellar development, enhances NMDAR-mediated currents and Ca(2+) influx in immature GCs before synapse formation. The VEGF receptor Flk1 forms a complex with the NMDAR subunits NR1 and NR2B. In response to VEGF, the number of Flk1/NR2B coclusters on the cell surface increases. Stimulation of Flk1 by VEGF activates Src-family kinases, which increases tyrosine phosphorylation of NR2B. Inhibition of Src-family kinases abolishes the VEGF-dependent NR2B phosphorylation and amplification of NMDAR-mediated currents and Ca(2+) influx in GCs. These findings identify VEGF as a modulator of NMDARs before synapse formation and highlight a link between an activity-independent neurovascular guidance cue (VEGF) and an activity-regulated neurotransmitter receptor (NMDAR).

Role of synectin in lymphatic development in zebrafish and frogs.

The molecular basis of lymphangiogenesis remains incompletely characterized. Here, we document a novel role for the PDZ domain-containing scaffold protein synectin in lymphangiogenesis using genetic studies in zebrafish and tadpoles. In zebrafish, the thoracic duct arises from parachordal lymphangioblast cells, which in turn derive from secondary lymphangiogenic sprouts from the posterior cardinal vein. Morpholino knockdown of synectin in zebrafish impaired formation of the thoracic duct, due to selective defects in lymphangiogenic but not angiogenic sprouting. Synectin genetically interacted with Vegfr3 and neuropilin-2a in regulating lymphangiogenesis. Silencing of synectin in tadpoles caused lymphatic defects due to an underdevelopment and impaired migration of Prox-1(+) lymphatic endothelial cells. Molecular analysis further revealed that synectin regulated Sox18-induced expression of Prox-1 and vascular endothelial growth factor C-induced migration of lymphatic endothelial cells in vitro. These findings reveal a novel role for synectin in lymphatic development.

Endothelial oxygen sensors regulate tumor vessel abnormalization by instructing phalanx endothelial cells.

An ancestral function of vessels is to conduct blood flow and supply oxygen (O(2)). In hypoxia, cells secrete angiogenic factors to initiate vessel sprouting. Angiogenic factors are balanced off by inhibitors, ensuring that vessels form optimally and supply sufficient oxygen (O(2)). By contrast, in tumors, excessive production of angiogenic factors induces vessels and their endothelial cell (EC) layer to become highly abnormal, thereby impairing tumor perfusion and oxygenation. In such pathological conditions, angiogenic factors act as "abnormalization factors" and promote the vessel "abnormalization switch." Recent genetic data indicate that ECs sense an imbalance in oxygen levels, by using the oxygen-sensing prolyl hydroxylase PHD2. In conditions of O(2) shortage, a decrease in PHD2 activity in ECs initiates a feedback that restores their shape, not their numbers. This induces ECs to align in a streamlined "phalanx" of tightly apposed, regularly ordered cobblestone ECs, which improves perfusion and oxygenation. As a result, EC normalization in PHD2 haplodeficient tumor vessels improves oxygenation and renders tumor cells less invasive and metastatic. This review discusses the role of PHD2 in the regulation of vessel (ab)normalization and the therapeutic potential of PHD2 inhibition for tumor invasiveness and metastasis.