Wnt signaling contributes the greatest impact in primary sex determination in the female. In the absence of a Y chromosome, low levels of Wnt and R-spondin 1 (Rspo1) are maintained by the transcription factors Wt1, Lhx1, GATA4 and Sf1. Wnt4 and Rspo1 can independently signal through different pathways to stabilize β catenin. β catenin, in turn, transcriptionally activates the genes that encode for Wnt4 and Rspo1, setting up a positive feedback loop.
β catenin activates genes necessary for the development of the ovary and suppresses Sox9, which is required for testis development. In the presence of a Y chromosome, Sox9 expression is elevated, which suppresses β catenin and leads to the activation of the testis-determining pathway.
Which of the following would lead to a sex reversion in an XY mouse fetus? Select ALL that apply.
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a. A knockout of the Wnt4 gene
b. A knockout of the Rspo1 gene
c. A knockout of the Sox9 gene
d. Pharmacological inhibition of β catenin
e. Use of a constitutively active β catenin
a. A knockout of the Wnt4 gene
b. A knockout of the Rspo1 gene
c. A knockout of the Sox9 gene
d. Pharmacological inhibition of β catenin
Sex reversion in an XY mouse fetus can occur through various mechanisms that disrupt the normal functioning of the Wnt signaling pathway and the balance between β catenin and Sox9. The following options would lead to sex reversion in an XY mouse fetus:
a. A knockout of the Wnt4 gene: Wnt4 is responsible for stabilizing β catenin and activating genes necessary for ovarian development. If the Wnt4 gene is knocked out, the positive feedback loop involving β catenin and Wnt4 will be disrupted, leading to sex reversion.
b. A knockout of the Rspo1 gene: Rspo1 is another factor that stabilizes β catenin and contributes to the activation of genes for ovarian development. A knockout of the Rspo1 gene will disrupt this process, leading to sex reversion.
c. A knockout of the Sox9 gene: Sox9 is required for testis development and suppresses the expression of β catenin. In the absence of Sox9, β catenin will not be suppressed, and the ovary-determining pathway will be activated, causing sex reversion.
d. Pharmacological inhibition of β catenin: Inhibiting the activity of β catenin would prevent its transcriptional activation of genes necessary for ovarian development. Without the activation of these genes, the testis-determining pathway will be activated, leading to sex reversion.
e. Use of a constitutively active β catenin: By using a constitutively active form of β catenin, its activity will not be regulated and it will constantly activate genes for ovarian development. This will disrupt the testis-determining pathway and lead to sex reversion.
Therefore, options a, b, c, d, and e would all lead to sex reversion in an XY mouse fetus.
To determine which of the given options would lead to sex reversion in an XY mouse fetus, we need to understand the role of each gene in primary sex determination.
In the absence of a Y chromosome, low levels of Wnt and R-spondin 1 (Rspo1) are maintained by transcription factors such as Wt1, Lhx1, GATA4, and Sf1. Wnt4 and Rspo1 can independently signal through different pathways to stabilize β-catenin, which then activates genes necessary for ovarian development and suppresses Sox9, required for testis development.
In the presence of a Y chromosome, Sox9 expression is elevated, suppressing β-catenin and activating the testis-determining pathway.
To have a sex reversion in an XY mouse fetus, we need to disrupt this delicate balance between Wnt signaling, β-catenin activation, and Sox9 suppression. The possible options and their effects are:
a. A knockout of the Wnt4 gene:
By knocking out the Wnt4 gene, there would be no Wnt4 protein available to activate the Wnt signaling pathway necessary for ovarian development. This absence of Wnt4 could lead to a sex reversion toward the male phenotype. Therefore, option a could lead to a sex reversion and should be selected.
b. A knockout of the Rspo1 gene:
Similarly, by knocking out the Rspo1 gene, there would be no Rspo1 protein available to activate the Wnt signaling pathway and stabilize β-catenin. This disruption in the Wnt signaling pathway could also lead to a sex reversion. Therefore, option b could lead to a sex reversion and should be selected.
c. A knockout of the Sox9 gene:
In this scenario, by knocking out the Sox9 gene, its suppression of β-catenin would be lost. This could lead to the activation of β-catenin and subsequently the ovarian development pathway. Hence, a knockout of the Sox9 gene could potentially prevent or reverse testis development, resulting in a sex reversion. Therefore, option c could lead to a sex reversion and should be selected.
d. Pharmacological inhibition of β-catenin:
Inhibiting β-catenin would prevent its activation and subsequent activation of genes necessary for ovarian development. Without optimal ovarian development, the fetus may undergo sex reversion toward the male phenotype. Therefore, option d could lead to a sex reversion and should be selected.
e. Use of a constitutively active β-catenin:
This option involves artificially activating β-catenin throughout development. However, since β-catenin activation suppresses Sox9, using a constitutively active β-catenin would likely prevent testis development and stabilize ovarian development. Thus, it would not lead to a sex reversion in an XY mouse fetus. Therefore, option e would not lead to a sex reversion and should not be selected.
Therefore, the options that could potentially lead to a sex reversion in an XY mouse fetus are:
a. A knockout of the Wnt4 gene
b. A knockout of the Rspo1 gene
c. A knockout of the Sox9 gene
d. Pharmacological inhibition of β-catenin