Box Extension 17.3

Sex Determination and Differentiation, Emphasizing Mammals

Animals use a variety of mechanisms to determine the sex of an individual. Sometimes, the sex of an individual is not hardwired by genes, but instead, environmental factors play major roles in sex determination. We have seen two examples earlier in this chapter: sex change based on harem formation or other social factors in certain fish, and determination of sex by the body temperature prevailing during embryonic development in sea turtles and some other nonavian reptiles. In mammals, sex is determined genetically.

The external genital structures of a mammalian embryo are said to be indifferent during early development because they have the potential to differentiate into either male or female structures. The indifferent state is illustrated in a 4-week-old human embryo at the top of Figure A. As the gonads develop, if they are testes, the genital tubercle is hormonally signaled to develop into the glans (“head”) of the penis, the labioscrotal swellings are signaled to develop into the scrotum, and the other primordia form male structures as well. If the gonads develop into ovaries, all these structures differentiate into female external genitalia. For example, the genital tubercle becomes the glans of the clitoris.

The gonads are also indifferent early in the development of a mammalian embryo: They can become either testes or ovaries. The indifferent gonads are positioned in the mid-abdomen. The gonads stay there throughout development in females. In males of most species of mammals, the gonads migrate away from their initial position as gestation proceeds, so that at birth they are either in the scrotum (as in humans) or poised to enter the scrotum.

Figure A Differentiation of the external genitalia Colors are used to identify homologous tissues. For example, the tissue labeled yellow is of the same developmental origin in all five drawings. In early development—as typified by a human embryo at 4 weeks of developmental age (seen at the top)—the external genital structures are identical regardless of an individual’s sex. In male embryos (XY), secretion of testosterone by the gonads when they differentiate causes the external genitalia to differentiate to become male in form, starting after the seventh week of gestation in humans. Without testosterone, the genitalia become female in form. The external genitalia can be definitively distinguished as male or female at about the twelfth week of human gestation.

Box Extension 17.3 discusses the sexual differentiation of internal structures at greater length. It also discusses the genetic and endocrine mechanisms that control sexual differentiation.

Early in mammalian development, each indifferent gonad is associated with two ducts, a Müllerian duct and Wolffian duct (Figure B). If the gonads differentiate into testes, the Wolffian duct on each side differentiates to form the epididymis, vas deferens, and seminal vesicle on that side, whereas the Müllerian ducts degenerate. If the gonads develop into ovaries, the Müllerian ducts differentiate into the oviducts and uterus, whereas the Wolffian ducts degenerate.

Figure B The Müllerian and Wolffian ducts at an early, sexually indifferent stage of embryonic development. These ducts differentially develop in the two sexes to give rise to the adult ducts that convey gametes away from the gonads. The Müllerian ducts never connect with the gonads during female development. Thus the mature ovaries are simply next to the openings of the oviducts (see Figure 17.10A).

Investigators discovered in the 1990s that a gene on the Y chromosome of mice and humans, the SRY gene, determines whether the undifferentiated gonads will become testes or ovaries. In mammals, individuals that inherit one Y chromosome (from their male parent) and one X chromosome (from their female parent) become males. Such individuals have the SRY gene. Individuals that inherit X chromosomes from both parents lack the SRY gene and become females.

The indifferent gonads and indifferent external genital structures of early embryos intrinsically differentiate into the female form unless induced to do otherwise. When the SRY gene is present in an embryo, expression of the gene sets in motion processes that result in the development of testes and other male structures.

How does the SRY gene induce the development of testes? In humans, around the 7th week of embryonic development, cells of the indifferent gonads in a genetically male embryo begin to transcribe and express the SRY gene, which codes for a protein called testis-determining factor (TDF). TDF interacts with the DNA of the indifferent gonadal cells to activate additional genes that direct cellular differentiation into testicular Sertoli and Leydig cells. Secretions of these cells then lead to the differentiation of the other male structures. The Sertoli cells secrete Müllerian-inhibiting substance (also called Müllerian-inhibiting hormone or anti-Müllerian hormone), which causes degeneration of the Müllerian ducts. The Leydig cells secrete testosterone, which promotes development of the Wolffian ducts. The testosterone and its metabolite dihydrotestosterone (DHT) also stimulate development of the penis and scrotum (see Figure A) and the prostate gland.

As already noted, the indifferent embryonic structures become female unless the SRY gene is expressed to specify male development. Estrogen does not appear to be required for initial sex determination in a female, although estrogen is crucial at puberty and beyond.