The Role of FGF9 and Proliferation in Sex Determination

The initiation of testis development in mammals depends on the presence or absence of the Y chromosome-linked gene, Sry. Much is known about the early morphological changes that are initiated downstream of Sry, yet the molecular targets of Sry and other molecular signals that direct early testis formation are largely unknown. Recently, fgf9 knockout mice were found to undergo male to female sex reversal: despite the presence of a Y chromosome, fgf9-/- XY mice form abnormal testes or ovaries. We have investigated the role fgf9 in male sex determination. Fgf9-/- gonads show a proliferation decrease in SFl-positive cells near the coelomic epithelium. This population gives rise to male-specific cell types such as Sertoli and Leydig cells. Later in gonad formation, fgf9-/- XY gonads continue to proliferate at a lower rate and have few or no Sertoli and Leydig cells, suggesting that sex reversal in fgf9-/- XY gonads may be caused by a reduction in the number of male-specific cell types that direct testis development. In cultured gonads, FGF9 induces proliferation of many cell types. FGF9 also induces other male-specific events in culture, such as an increase in laminin deposition, the migration of vascular cells, and the formation of a male vascular pattern. However, FGF9 does not induce Sertoli differentiation, indicating that although FGF9 is part of the pathway for male sex determination, it is not the only piece.