GSK-3ß: a signaling pathway node modulating neural stem cell and endothelial cell interactions.

The neurogenic areas of the brain are highly organized structures in which there is dynamic reciprocal modulation of neural stem cells (NSC) and microvascular endothelial cells (BEC) resulting in control of neural stem cell and vascular proliferation, survival and differentiation throughout the life of the individual. Select molecules such as GSK-3ß, functioning as signaling nodes, and their downstream signaling components including HIF-1α, HIF-2α and ß-catenin participate in regulating and orchestrating the diverse responses involved in this complex process. In this report we demonstrate GSK-3ß's role as a signaling node in two mouse strains (C57BL/6, which have been found to respond to and recover from a hypoxic insult from P3 to P11 poorly and CD-1, which have been found to respond to and recover from a hypoxic insult from P3 to P11 well both in vivo and in vitro) which mimic the wide range of responsiveness to hypoxic insult observed in the very low birth weight premature infant population. Differences in levels of neural stem cell and microvascular endothelial cell GSK-3ß activation, ß-catenin serine phosphorylation, HIF-1α and 2α, BDNF, SDF-1 and VEGF, ß-III-tubulin and cleaved notch-1 expression in C57BL/6 and CD-1 subventricular zone tissues, and cultured NSC and BEC were noted. Specifically, CD1 pups, SVZ tissues and isolated NSC and BEC exhibit less GSK-3ß and ß-catenin serine phoslphorylation and greater HIF-1α and 2α, BDNF, SDF-1 and VEGF, ß-III-tubulin and cleaved notch-1 expression compared to C57BL/6. Correlating with these changes were differences of several neural stem cell and microvascular endothelial cell behaviors including proliferation, apoptosis, migration and differentiation with CD1 NSC exhibiting greater proliferation and migration and decreased apoptosis and differentiation and CD1 BEC exhibiting greater angiogenesis. Further, upon treatment with nanomolar concentrations of a GSK-3ß inhibitor (SB412682), C57 NSC and BEC behaviors could be brought to CD1 levels, consistent with the concept of GSK-3ß functioning as a multifunctional signaling pathway node, modulating several behaviors in these cells. Lastly, the therapeutic potential of targeting GSK-3ß is discussed.