Primordial Germ Cells Migrate into the Developing Gonad

In most animals, including many vertebrates, the unfertilized egg is asymmetrical, with different regions of cytoplasm containing different sets of mRNA and protein molecules (discussed in Chapter 21). When the egg is fertilized and divides repeatedly to produce the cells of the early embryo, the cells that inherit specific molecules localized in a particular region of the egg cytoplasm become primordial germ cells. In mammals, by contrast, the egg is more symmetrical, and the cells produced by the first few divisions of the fertilized egg are all totipotent—that is, they can give rise to any of the cell types in the body, including germ cells. A small group of cells in the early mammalian embryo is induced to become primordial germ cells by signals produced by neighboring cells. In mice, for example, 1 week after fertilization, about 50 cells in tissue lying outside the embryo proper are induced by their neighbors to become primordial germ cells. In the next few days, these cells proliferate and are swept back into the embryo proper along with the invaginating hindgut. They then actively migrate through the gut to their final destination in the developing gonads (Figure 20-16). As the primordial germ cells migrate through the embryo, they are signaled to survive, proliferate, and migrate by various extracellular proteins produced by adjacent somatic cells.

Figure 20-16

Migration of mammalian primordial germ cells. (A) Drawing showing the final stages of migration through the hindgut into the two genital ridges, each of which will develop into a gonad—either an ovary or a testis. (B) Micrograph showing migrating (more...)

After the primordial germ cells enter the developing mouse gonad, which at this stage is called the genital ridge, they continue to proliferate for 2 or 3 more days. At this point, they commit to a developmental pathway that will lead them to become either eggs or sperm, depending not on their own sex chromosome constitution but on whether the genital ridge has begun to develop into an ovary or a testis, respectively. The sex chromosomes in the somatic cells of the genital ridge determine which type of gonad the ridge becomes. A single gene on the Y chromosome has an especially important role in this decision.

The Sry Gene on the Y Chromosome Can Redirect a Female Embryo to Become a Male

Aristotle believed that the temperature of the male during sexual intercourse determined the sex of offspring: the higher the temperature, the greater the chance of producing a male. We now know that the sex of a mammal is determined by its sex chromosomes, rather than by the environment (although for some animals, such as crocodiles and many fish, the opposite is true). Female mammals have two X chromosomes in all of their somatic cells, whereas males have one X and one Y. The Y chromosome is the determining factor. Individuals with a Y chromosome develop as males no matter how many X chromosomes they have, whereas individuals without a Y chromosome develop as females, even if they have only one X chromosome. The sperm that fertilizes the egg determines the sex of the resulting zygote: eggs have a single X chromosome, whereas the sperm can have either an X or a Y.

The Y chromosome influences the sex of the individual by inducing the somatic cells of the genital ridge to develop into a testis instead of an ovary. The crucial gene on the Y chromosome that has this testis determining function is called Sry , for “sex-determining region of Y.” Remarkably, when this gene is introduced into the genome of an XX mouse zygote, the transgenic embryo produced develops as a male, even though it lacks all of the other genes on the Y chromosome (Figure 20-17). Such mice, however, cannot produce sperm, in part, at least, because the presence of two X chromosomes suppresses sperm development.

Figure 20-17

The Sry gene, injected into the nucleus of an XX female zygote, caused the transgenic embryo produced to develop into a male. The external genitalia of the transgenic mouse are indistinguishable from those of a normal XY male mouse. (From P. Koopman et (more...)

Sry is expressed only in a subset of the somatic cells of the developing gonad, and it causes these cells to differentiate into Sertoli cells, which are the main type of supporting cells found in the testis. The Sertoli cells direct sexual development along a male pathway by affecting other cells in the genital ridge in at least four ways:

1.

They stimulate the newly arriving primordial germ cells to develop along a pathway that produces sperm.

2.

They secrete anti-Müllerian hormone, which suppresses the development of the female reproductive tract by causing the Müllerian duct to regress (this duct otherwise gives rise to the oviduct, uterus, and upper part of the vagina).

3.

They stimulate particular somatic cells that lie adjacent to the developing gonad to migrate into the gonad and form critical connective tissue structures that are required for normal sperm production.

4.

They help to induce other somatic cells in the developing gonad to become Leydig cells, which secrete the male sex hormone testosterone; this hormone is responsible for inducing all male secondary sexual characteristics. These include the structures of the male reproductive tract, such as the prostate and seminal vesicles, which develop from another duct, called the Wolffian duct system. This duct system degenerates in the developing female because it requires testosterone to survive and develop. The testosterone also masculinizes the early developing brain and thereby plays a major part in determining male sexual identity and orientation, and thereby behavior: female rats that are treated with testosterone around birth, for example, later display malelike sexual behavior.

Sry encodes a gene-regulatory protein (Sry) that activates the transcription of other gene-regulatory proteins required for Sertoli cell development, including the Sry-related protein Sox9. In the absence of either Sry or Sox9, the genital ridge develops into an ovary. The supporting cells become follicle cells instead of Sertoli cells. Other somatic cells become theca cells instead of Leydig cells and, beginning at puberty secrete the female sex hormone estrogen instead of testosterone. The primordial germ cells develop into eggs instead of sperm (Figure 20-18, and see Figure 20-28), and the animal develops as a female.

Figure 20-18

Influence of Sry on gonad development. The germ line cells are shaded in red, and the somatic cells are shaded in green and blue. The change from light to darker color indicates that the cell has matured or differentiated. The Sry gene acts in a subpopulation (more...)

If the genital ridges are removed before they have started to develop into testes or ovaries, a mammal develops into a female, regardless of the sex chromosomes it carries. It seems that female development is the “default” pathway of sexual development in mammals.

Summary

A small number of cells in the gastrulating mammalian embryo are signaled by their neighbors to become primordial germ cells. These cells migrate into the genital ridges, which develop into the gonads. Here, the primordial germ cells start to develop into either eggs, if the gonad is becoming an ovary, or sperm, if the gonad is becoming a testis. A developing gonad will develop into an ovary unless its somatic cells contain a Y chromosome, in which case it develops into a testis. The Sry gene on the Y chromosome is responsible for this testis-determining function: it is expressed in a subset of somatic cells in the developing gonad, and it induces these cells to differentiate into Sertoli cells. The Sertoli cells in turn produce the signal molecules that promote the development of male characteristics, suppress the development of female characteristics, and induce the primordial germ cells to commit to sperm development.