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dc.contributor.advisor Capel, Blanche en_US
dc.contributor.author Jameson, Samantha Ann en_US
dc.date.accessioned 2012-01-10T16:00:11Z
dc.date.available 2013-12-30T05:30:08Z
dc.date.issued 2011 en_US
dc.identifier.uri http://hdl.handle.net/10161/5028
dc.description Dissertation en_US
dc.description.abstract <p>The divergence of distinct cell populations from multipotent progenitors is poorly understood, particularly <italic>in vivo</italic>. The gonad is an ideal place to study this process because it originates as a bipotential primordium where multiple distinct lineages acquire sex-specific fates as the organ differentiates as a testis or an ovary. The early gonad is composed of four lineages: supporting cells, interstitial/stromal cells, germ cells, and endothelial cells. Each lineage in the early gonad consists of bipotential progenitors capable of adopting either a male or female fate, which they do in a coordinated manner to form a functional testis or ovary. The supporting cell lineage is of particular interest because the decision of these cells to adopt the male or female fate dictates the fate of the gonad as a whole. </p><p><p>To gain a more detailed understanding of the process of gonadal differentiation at the level of the individual cell populations, we conducted microarrays on sorted cells of the four lineages from XX and XY mouse gonads at three time points spanning the period when the gonadal cells transition from sexually undifferentiated progenitors to their respective sex-specific fates. Our analysis identified genes specifically depleted and enriched in each lineage as it underwent sex-specific differentiation. We also determined that the sexually undifferentiated germ cell and supporting cell progenitors showed lineage priming. Multipotent progenitors that show lineage priming express markers of the various fates into which they can differentiate and subsequently silence genes associated with the fate not adopted as they differentiate. We found that germ cell progenitors were primed with a bias toward the male fate. In contrast, supporting cell progenitors were primed with a female bias. This yields new insights into the mechanisms by which different cell types in a single organ adopt their respective fates. </p><p><p>We also used a genetic approach to investigate how individual factors contribute to the adoption of the male supporting cell fate. We previously demonstrated that <italic>Fgf9</italic> and <italic>Wnt4</italic> act as mutually antagonistic factors to promote male or female development of the bipotential mammalian gonad. <italic>Fgf9</italic> is necessary to maintain <italic>Sox9</italic> expression, which drives male development. However, whether FGF9 acted directly on <italic>Sox9</italic> or indirectly through repression of <italic>Wnt4</italic>, was unknown. <italic>Wnt4</italic> is a female-primed gene, and is therefore repressed during male development. To determine how <italic>Fgf9</italic> functioned, we generated double <italic>Fgf9/Wnt4</italic> and <italic>Fgfr2/Wnt4</italic> mutants. While single XY <italic>Fgf9</italic> and <italic>Fgfr2</italic> mutants showed partial or complete male-to-female sex reversal, loss of <italic>Wnt4</italic> in an <italic>Fgf9</italic> or <italic>Fgfr2</italic> mutant background rescued normal testis development. We also found that <italic>Wnt4</italic> and another female-associated gene (<italic>Rspo1</italic>) were derepressed in <italic>Fgf9</italic> mutants prior to the down-regulation of <italic>Sox9</italic>. Thus, the primary function of <italic>Fgf9</italic> is the repression of female genes, including <italic>Wnt4</italic>. We also tested the reciprocal possibility: that de-repression of <italic>Fgf9</italic> was responsible for the aspects of male development observed in XX <italic>Wnt4</italic> mutants. However, we show that loss of <italic>Fgf9</italic> in XX <italic>Wnt4<super>-/-</super></italic> gonads does not rescue the partial female-to-male sex reversal. </p><p><p>Based on the <italic>Fgf9/Wnt4</italic> double mutant studies, we propose a two part model of male sex determination in which both the activation of male genes and repression of female genes is required. Also, this work demonstrates that the repression of the female-primed gene <italic>Wnt4</italic> is required for male development, and <italic>Fgf9</italic> is one factor that leads to the repression of female-primed genes.</p> en_US
dc.subject Cellular biology en_US
dc.subject cell fate en_US
dc.subject Fgf9 en_US
dc.subject gonad en_US
dc.subject lineage priming en_US
dc.subject sex determination en_US
dc.subject Wnt4 en_US
dc.title Understanding Cell Fate Decisions in the Embryonic Gonad en_US
dc.type Dissertation en_US
dc.department Cell Biology en_US
duke.embargo.months 24 en_US

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