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Lecture 13

DEV2011: Lecture 13 summary

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Monash University

LECTURE 13 Sex Determination: Sex determination is the initial event that determines whether the gonads will develop as testes or ovaries. XY system in mammals: Sex is determined by presence of Y. "Female" is the default sex; due to the absence of the Y. The combination of sex chromosomes that determine the sex of an offspring; in humans the sex chromosomes of a normal female are XX and the sex chromosomes of a normal male are XY. SRY: Sry is a sex-determining gene on the Y chromosome. During gestation, the cells of the primordial gonad that lie along the urogenital ridge are in a bipotential state, meaning they possess the ability to become either male cells (Sertoli and Leydig cells) or female cells (follicle cells and Theca cells). SRY initiates testis differentiation by activating male-specific transcription factors that allow these bipotential cells to differentiate and proliferate. SRY accomplishes this by upregulating SOX9, a transcription factor with a DNA-binding site very similar to SRY's. SOX9 in turn upregulates fibroblast growth factor 9 (Fgf9), which is necessary for proper Sertoli cell differentiation. Fgf9 then feeds back and upregulates SOX9. SOX9 can also upregulate itself by binding to its own enhancer region (positive feedback loop). Once proper SOX9 levels are reached, the bipotential cells of the gonad begin to differentiate into Sertoli cells. Additionally, cells expressing SRY will continue to proliferate to form the primordial testis. While this constitutes the basic series of events, this brief review should be taken with caution since there are many more factors that influence sex differentiation. SOX9: Mutations in Sox9 or any associated genes can cause reversal of gender or even hermaphroditism. If Fgf9, which is activated by Sox9, isn’t present, a fetus with the both X and Y chromosomes can be converted into a female. The related problem of hermaphroditism can be caused by unusual activity of the SRY, usually when it's translocated onto the X-chromosome and its activity is only activated in some cells. SOX-9 also plays a pivotal role in male sexual development; by working with Sf1, SOX-9 can produce AMH in Sertoli cells to inhibit the creation of a female reproductive system. [3It also interacts with a few other genes to promote the development of male sexual organs. Dax1: Dax1 plays an important role in the normal development of several hormone- producing tissues. These tissues include the adrenal glands, the pituitary gland and hypothalamus which are located in the brain and the male and female reproductive structures (the testes and ovaries). DAX1 controls the activity of certain genes in the cells that form these tissues during embryonic development. Proteins that control the activity of other genes are known as transcription factors. DAX1 also plays a role in regulating hormone production in these tissues after they have been formed. Wnt4: WNT4 is a secreted protein that in humans is encoded by the Wnt4 gene, found on chromosome 1. It promotes female sex development and represses male sex development. Loss of function can have serious consequences, such as female to male sex reversal. Gonads arise from the thickening of coelomic epithelium, which at first appears as multiple cell layers. They later commit to sex determination, becoming either female or male under normal circumstances. Regardless of sex, though, WNT4 is needed for cell proliferation.[4]In mouse gonads, it has been detected only eleven days after fertilization. If deficient in XY mice, there is a delay in Sertoli cell
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