The goal of this project is to understand the interplay between vascular development and organogenesis, using the developing mouse testis as a model system. Vascular systems are highly specialized for the functional needs of different organs, but precisely how the tissue and blood vessels interact to achieve this integration is not known. Traditionally, the vasculature has been considered to play a passive role, simply as a source of oxygen and nutrients for developing organs. In contrast, we hypothesize that the vasculature plays an interactive role in organ development: Not only does an organ shape its vasculature, but signals from the vasculature actively influence the pattern, organization, and differentiation of an organ. Much of the work on vascular signaling has been done in cell culture systems and few models exist to study the development of the vasculature in the context of an intact organ. The bipotential gonad is an excellent model system to achieve this goal. Because development of the testis or ovary diverges from an identical primordium, comparative studies can be used to identify relevant signaling pathways. In addition, we have developed an organ culture system in which signals that control vascular development can be blocked or induced without the normal lethality associated with disruption of this critical system in the whole animal. In the first years of this grant, we characterized the early formation of the arterial system in the testis, and identified several signaling pathways involved in the divergence of male and female vascular systems. In the next five years, we plan to investigate the unconventional idea that the vasculature plays an active role in the development of the testis. We will use both genetic mutants and in vitro techniques to determine the function of vascular development in the patterning of testis cords and the differentiation of testis cell types. In addition, we plan to characterize the role of candidate signaling pathways (Fgf, Pdgf, Wnt, Fst, Bmp) in inducing this process in the testis, or blocking it in the ovary. Using genetic mutants and microarray technology, we will identify new genes that control the formation of the male-specific coelomic vessel. The study of how vascular specialization is regulated and integrated with organ development has significance beyond the fields of ovary and testis formation, in broader fields of organogenesis, endocrinology, and vascular biology. In addition, the molecular signals that control or repress the growth of vasculature into a tissue are of critical concern for the design of therapies in the fields of wound healing and tumor biology. ? ?
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