From Sry to Z: Cellular and molecular mechanisms of testis development.

摘要

Development of the mammalian gonad represents a unique biological system where a balance of factors governs the specification of either a testis or an ovary from the bipotential tissue of the genital ridge. Sry, the sex-determining gene on the Y chromosome, is recognized as the genetic switch that initiates a cascade of sex-specific cellular events leading to the development of a testis. Thus far, no direct targets of Sry have been discovered. Characterization of the cellular events activated by Sry has been a major goal of our lab. We have analyzed in detail three primary cellular pathways downstream of Sry: cell proliferation, cell migration, and vascularization. Identification of the genes controlling these events has contributed a great deal to our knowledge of the sex determination pathway in mammals.;The main focus of my thesis research involved the characterizing of vascular development in the XY versus the XX gonad. The goal of this work was to determine the functional role of sex-specific vascular development to contribute to a general understanding of how specialization of the vasculature occurs during organogenesis. I compared mechanisms of vascular growth in XX and XY gonads and found that although primary growth of the vasculature is similar in XX and XY gonads, an additional level of complexity is evident in the XY vasculature, which is modified by the addition of migrating vascular cells from the adjacent mesonephros. Migrating cells contribute to an arterial network that is established sex-specifically in the XY gonad as venous differentiation is repressed. This vascular organization contributes to the establishment of an alternate pattern of XY blood flow between 11.5--12.5 dpc. We propose that the arterial differentiation and remodeling of blood flow in the XY gonad may provide an efficient means to collect and export testosterone for masculinizing the XY embryo. By examining embryonic XX gonads mutant for the signaling molecule Wnt4, we uncovered a novel role for Wnt4 in the female gonad that actively represses migration and assembly of the male specific vasculature.;As part of my thesis I also investigated the role of PDGF signaling in the XY gonad to determine if this pathway is important for vascular development in the testis as has been shown in other developing organs. I characterized the expression patterns of PDGF family members and analyzed the phenotype of Pdgfr alpha -/- gonads. This revealed that PDGF signaling is required for promoting endothelial migration and organization as well as male specific proliferation and development of steroid-secreting Leydig cells. I have also examined the interaction of Pdgf signaling with the Dhh and Wnt signaling pathways, two other pathways involved in Leydig cell and vascular development. (Abstract shortened by UMI.).