This new laboratory is tackling a fundamental problem in the nervous and vascular system: how these two systems with distinct functions but similar anatomical architecture are established during development? To study this question, we have now focused on developing interaction between these two systems, particularly neuronal influences on vascular identity such as artery, vein and lymphatic vessels and branching pattern, and vascular influences on the maintenance of stem cell capacity in neural stem cells (NSCs) in the developing brain and spinal cord, and the adult brain (subventricular zone and hippocampus), and in hematopoietic stem cells (HSCs) in the fetal liver and adult bone marrow (BM). Our previous studies demonstrated that in developing skin arteries are aligned with peripheral nerves. In the absence of nerve, arteries fail to differentiate properly. Strikingly, the disorganized pattern of nerve changes the branching pattern of arteries. These data suggest that nerve-derived signals are required for proper arterial differentiation and branching pattern of arteries in the skin. We also discovered that vascular endothelial growth factor-A (VEGF-A) that is secreted from both neurons and Schwann cells in the peripheral nerve controls arterial differentiation in vitro and in vivo. Surprisingly, mutations that inactivate VEGF signals cause defective arterial differentiation but no significant defect in the nerve-blood vessel alignment. This suggests that such alignment is mediated by different nerve-derived signals from VEGF-A. We seek to define the nerve-derived signals to control the branching pattern of arterial vessels. Efforts to identify the signals are underway using microarrays and signal trap secreted molecule screening from purified peripheral neurons and Schwann cells. Candidate molecules are tested by gain- and loss-of-function gene manipulations in in vitro co-culture of mouse embryonic endothelial cells with neurons or Schwann cells, and in mouse embryos. In parallel with these studies, we seek to understand the molecular mechanisms that develop branching pattern from primary vasculature. We are also using the gain- and loss-of-function gene manipulations and in vivo transplantation in chick and mouse embryos.? We are interested in the maintenance of stem cells, and more specifically we are trying to understand the role of blood vessels as niche for stem cells. Recent studies have demonstrated that blood vessels support the maintenance of NSCs and promote neurogenesis in the bran. Currently, we are focusing on identifying molecules that are expressed in brain endothelial cells and support NSCs, using miroarrays. We also try to develop in vivo imaging of HSCs using multiple combinations of fluorescent proteins that are controlled by enhancers/promoters actively in HSCs and/or progenitors. This developing tool may lead to the study of niche for HSCs that can be used to identify cells and signals to support HSCs in the BM.
