Neural induction of the blood-brain barrier: still an enigma.

1. The study of the blood-brain barrier and its various realms offers a myriad of opportunities for scientific exploration. This review focuses on two of these areas in particular: the induction of the blood-brain barrier and the molecular mechanisms underlying this developmental process. 2. The creation of the blood-brain barrier is considered a specific step in the differentiation of cerebral capillary endothelial cells, resulting in a number of biochemical and functional alterations. Although the specific endothelial properties which maintain the homeostasis in the central nervous system necessary for neuronal function have been well described, the inductive mechanisms which trigger blood-brain barrier establishment in capillary endothelial cells are unknown. 3. The timetable of blood-brain barrier formation is still a matter of debate, caused largely by the use of varying experimental systems and by the general difficulty of quantitatively measuring the degree of blood-brain barrier "tightness." However, there is a general consensus that a gradual formation of the blood-brain barrier starts shortly after intraneural neovascularization and that the neural microenvironment (neurons and/or astrocytes) plays a key role in inducing blood-brain barrier function in capillary endothelial cells. This view stems from numerous in vitro experiments using mostly cocultures of capillary endothelial cells and astrocytes and assays for easily measurable blood-brain barrier markers. In vivo, there are great difficulties in proving the inductive influence of the neuronal environment. Also dealt with in this article are brain tumors, the least understood in vivo systems, and the induction or noninduction of barrier function in the newly established tumor vascularization. 4. Finally, this review tries to elucidate the question concerning the nature of the inductive signal eliciting blood-brain barrier formation in the cerebral microvasculature.