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SEX DETERMINATION AND DIFFERENTIATION
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Development of the Bipotential Urogenital (Gonadal) Ridge
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An overview of human sex determination and differentiation is depicted in Figures 36-1 and 36-2. The genetic sex of an infant is determined by which paternal sex chromosome, X or Y, was inherited.1,2,3 Sex determination refers to gonad differentiation that culminates with the developmental choice of the bipotential and undifferentiated gonad to become either testis or ovary. Sex differentiation refers to the developmental events that occur after the gonads have differentiated, for instance the formation of the penis or the clitoris.
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The early stages of sex determination, equivalent in mammals to gonadal determination, begin when primordial germ cells migrate from the yolk sac to the undifferentiated urogenital ridge on the mesonephric bulge between the 6th and 7th weeks of gestation (between 4 and 5 weeks post-fertilization). The differentiation of these cells from the intermediate mesoderm is dependent on the transcriptional activity of several transcription factors whose roles remain poorly understood.
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Mouse genetic models have implicated several ubiquitously expressed homeobox genes (Lhx9, Emx2, M33), transcription factors (Sf1, GATA4), and growth factor signaling genes (Ir, Igf1r, Irr, Fgf9) in the development and maintenance of the urogenital ridge,4,5,6 largely by promoting cell proliferation and preventing apoptosis. Studies of human mutations have paralleled some of the mouse data. For instance, the transcription factors Wilms tumor 1 (WT-1) and steroidogenic factor 1 (SF-1) demonstrate high transcriptional activity in the bipotential gonadal ridge prior to gonadal differentiation, and inactivating mutations of the corresponding genes in humans affect the ...