We have designed a novel system in which we can identify and study the signaling events and morphological changes that control the development of specialized vasculature in organs. The bi-potential development of the gonad provides a unique model system. The primitive vasculature in the gonad is identical between males and females until activation of the Y-linked sex-determining gene. Sry, initiates the morphological divergence of testis development. Our novel organ culture system reveals that during and following the window of Sry activity, endothelial and smooth muscle cells are recruited into the XY gonad from the attached mesonephros, whereas, no vascular migration occurs into the XX gonad. The divergence of vascular developmental pathways in the gonad provides a system in which comparative approaches can be used to identify structural specializations of the vasculature between XX and XY gonads and link them to signaling differences that arise that Sry expression. We will test the following hypotheses: . There are different mechanisms shaping vascular development in the gonad. These result in ovary or testis-specific structural specializations of the vasculature. . There are early functional requirements in the male embryo (e.g. hormone expert) that are reflected in specializations of the testing vasculature. . Sry activates male-specific signaling factors that control vascular specifications. By comparing expression patterns during X and XY gonads directly after SRY initiates the male pathway, we have identified several candidate signaling molecules that show activation differences between XX and XY gonads. Our organ culture system provides a direct means to test the effect of candidate factors on cell migration and vascular development. This work will yield important information about the signaling basis of heterogeneity in the formation and structure of ovary versus testis vasculature. Moreover, it serves as a general model of how the development of diverse vascular phenotypes is signaled and integrated with organogenesis throughout the embryo.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL063054-03
Application #
6390426
Study Section
Reproductive Biology Study Section (REB)
Program Officer
Goldman, Stephen
Project Start
1999-06-01
Project End
2003-05-31
Budget Start
2001-06-01
Budget End
2002-05-31
Support Year
3
Fiscal Year
2001
Total Cost
$193,811
Indirect Cost
Name
Duke University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
Cool, Jonah; DeFalco, Tony J; Capel, Blanche (2011) Vascular-mesenchymal cross-talk through Vegf and Pdgf drives organ patterning. Proc Natl Acad Sci U S A 108:167-72
DeFalco, Tony; Capel, Blanche (2009) Gonad morphogenesis in vertebrates: divergent means to a convergent end. Annu Rev Cell Dev Biol 25:457-82
Cook, Matthew S; Coveney, Douglas; Batchvarov, Iordan et al. (2009) BAX-mediated cell death affects early germ cell loss and incidence of testicular teratomas in Dnd1(Ter/Ter) mice. Dev Biol 328:377-83
Cool, J; Carmona, F D; Szucsik, J C et al. (2008) Peritubular myoid cells are not the migrating population required for testis cord formation in the XY gonad. Sex Dev 2:128-33
Barske, Lindsey A; Capel, Blanche (2008) Blurring the edges in vertebrate sex determination. Curr Opin Genet Dev 18:499-505
Coveney, Douglas; Ross, Andrea J; Slone, Jesse D et al. (2008) A microarray analysis of the XX Wnt4 mutant gonad targeted at the identification of genes involved in testis vascular differentiation. Gene Expr Patterns 8:529-37
Coveney, Douglas; Cool, Jonah; Oliver, Tim et al. (2008) Four-dimensional analysis of vascularization during primary development of an organ, the gonad. Proc Natl Acad Sci U S A 105:7212-7
Tang, Hao; Brennan, Jennifer; Karl, Jeannie et al. (2008) Notch signaling maintains Leydig progenitor cells in the mouse testis. Development 135:3745-53
Kim, Yuna; Bingham, Nathan; Sekido, Ryohei et al. (2007) Fibroblast growth factor receptor 2 regulates proliferation and Sertoli differentiation during male sex determination. Proc Natl Acad Sci U S A 104:16558-63
Coveney, Douglas; Ross, Andrea J; Slone, Jesse D et al. (2007) A microarray analysis of the XX Wnt4 mutant gonad targeted at the identification of genes involved in testis vascular differentiation. Gene Expr Patterns 7:82-92

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