In mice, the X-linked dominant mutation Testicular feminization (Tfm) eliminates the normal response to the testicular hormone testosterone during sexual differentiation. An XY mouse bearing the Tfm allele on the X chromosome develops testes, but no further male differentiation occurs—the external genitalia of such an animal are female. From this information, what might you conclude about the role of the Tfm gene product and the X and Y chromosomes in sex determination and sexual differentiation in mammals? Can you devise an experiment, assuming you can 'genetically engineer' the chromosomes of mice, to test and confirm your explanation?

Verified step by step guidance

1. Step 1: Understand the biological context—In mammals, sex determination is typically controlled by the presence of the Y chromosome, specifically the SRY gene, which initiates testis development. The X chromosome carries genes important for sexual differentiation, such as the Tfm gene, which is X-linked dominant and affects the response to testosterone.
2. Step 2: Analyze the phenotype of the Tfm mutation—An XY mouse with the Tfm mutation develops testes (indicating that the Y chromosome and SRY gene function normally to initiate testis formation), but the external genitalia are female, showing that the mutation disrupts the response to testosterone, preventing male differentiation despite the presence of testes.
3. Step 3: Formulate a hypothesis about the Tfm gene product—Since the mutation eliminates the normal response to testosterone, the Tfm gene product likely encodes the androgen receptor or a critical component of the testosterone signaling pathway necessary for male sexual differentiation after testis formation.
4. Step 4: Design an experiment to test the hypothesis—Using genetic engineering, create mice with different combinations of sex chromosomes and Tfm alleles, such as: (a) XY mice with a normal X chromosome, (b) XY mice with the Tfm mutation, (c) XX mice with the Tfm mutation, and (d) XY mice with a Y chromosome lacking SRY but carrying a normal X. Observe the sexual phenotype and hormone responses in each case to confirm the role of the Tfm gene product and the influence of X and Y chromosomes.
5. Step 5: Predict outcomes and interpret results—If the Tfm gene product is the androgen receptor, then mice with the Tfm mutation will fail to masculinize external genitalia despite having testes, confirming that the Y chromosome initiates testis development but the X-linked Tfm gene is essential for testosterone response and male differentiation.

Key Concepts

X-linked Dominant Mutations and Their Effects

X-linked dominant mutations occur on the X chromosome and can affect both males and females, but males are often more severely impacted due to having only one X. The Tfm mutation disrupts the normal function of the androgen receptor, preventing cells from responding to testosterone, which is crucial for male sexual differentiation despite the presence of testes.

Role of Sex Chromosomes in Mammalian Sex Determination

In mammals, the presence of the Y chromosome, specifically the SRY gene, initiates testis development, determining genetic sex as male (XY). However, sexual differentiation depends on hormone signaling pathways, where the X chromosome carries genes like the androgen receptor that mediate the body's response to male hormones.

Experimental Design Using Genetic Engineering to Test Gene Function

To test the role of the Tfm gene product, one could engineer mice with modified X chromosomes carrying either the normal or mutant allele and observe sexual differentiation outcomes. For example, introducing a functional androgen receptor gene into Tfm XY mice should restore male differentiation, confirming the gene's role in hormone response.