Homeostasis of the neural environment is indispensable for the normal functioning of neural cells, and is maintained by the blood-brain barrier (BBB). The BBB is induced during embryonic development. The present study aimed to clarify the molecular mechanisms of BBB induction in neural tissues. Using an in vivo model of BBB induction that is based on xenograft transplantation between quail and chick embryos, we showed that the gene expression in developing brain cells is appropriately regulated to generate the neural microenvironment for endothelial cells to form the neural tissue-specific vascular structure with a BBB function. Vascular endothelial growth factor (VEGF) is a factor controlling vascular proliferation as well as vascular permeability, and is known to be produced by developing brain cells. In the present study, we show that the isoforms of VEGF produced by developing quail brain cells change with close temporal correlation to the BBB induction. Among four isoforms, VEGF122 and VEGF166 were expressed constitutively during the course of embryonic development, while the expressions of VEGF146 and VEGF190 were upregulated after the differentiation of endothelial cells to BBB-forming cells had begun. Furthermore, through investigation into developing extracranial tissues, the changes in VEGF isoform expression, especially the upregulation of VEGF146 expression, were shown to be specific for brain tissues that contain the blood vessels with BBB properties. These results suggest that the expression of VEGF isoforms by brain cells is developmentally regulated for the achievement of brain development including the BBB induction.

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