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Sex Determination - Mammalian Mechanisms, Nonmammalian Mechanisms

developmental chromosome genetic male female sry develop

Sex determination refers to the mechanisms employed by organisms to produce offspring that are of two different sexes. First we present an overview of the sex determination mechanisms used by mammals. Then we discuss the great variety of mechanisms used by animals other than mammals.

A developing mammalian embryo's gender is determined by two sequential processes known as primary and secondary sex determination.

Primary Sex Determination.

Early in an embryo's development (four weeks after fertilization, in humans), two groups of cells become organized into the gonad rudiment that will eventually develop into either the ovaries or testicles. These gonads will eventually be the source of gametes in the adult. However, at this early stage they are unstructured organs that lack sex-specific features but have the potential to develop into gonads.

The first visible indication of sex-specific development, occurring in week seven in humans, is in males, with the gonads restructuring into two distinct compartments: the testicular cords and the interstitial region. In females, the gonads appear to lack distinct structures until later in development. Primary sex determination, including the differentiation of an embryo's gonads, is dependent on genetic factors associated with the embryo's sex chromosomes.

Secondary Sex Determination.

Secondary sex determination involves the development of additional sex-specific characteristics, such as the genitalia. This secondary pathway is controlled by sex-specific hormones that are Early in development, every fetus has two sets of primitive ducts. Under the influence of testosterone and the hormone AMH, the Wolffian ducts develop into the male vas deferens and accessory structures. Without testosterone or AMH, the Wolffian ducts degenerate and the Müllerian ducts develop into the female fallopian tubes, uterus, cervix, and upper vagina. secreted by the differentiated gonad. These hormones influence the sex differentiation of other parts of the body, including two pairs of ducts present in all developing embryos: the Müllerian ducts and the Wolffian ducts.

Testicles produce Müllerian inhibiting substance, a hormone that causes the Müllerian duct to degenerate. They also produce testosterone, which causes the Wolffian duct to develop into the internal male genitalia, such as the seminal vesicles and the vas deferens. Testosterone also promotes the development of the external male genitalia, including the penis, and it reduces the development of the breasts.

In females, where there are no testicles and where there is therefore no Müllerian inhibiting substance, the Müllerian duct differentiates into internal female genitalia: the fallopian tubes, uterus, and cervix.

Discovering the Testis-Determining Factor.

The different effects of the primary and secondary sex determination pathways was demonstrated by embryological transplant experiments carried out by Alfred Jost in the 1940s at the Collége de France in Paris, France. When Jost placed an undifferentiated gonad from a male rabbit next to an undifferentiated gonad inside a female fetus, the gonad from the female developed into an ovary, and the gonad from the male developed into a testicle, as it would have done inside the male. Hence, the sex of the gonad was dependent upon its genotype (XX or XY) and is a result of primary sex determination. The genitalia of these experimental animals revealed the influence of secondary sex determination mechanisms. Under the conflicting signal of the two gonads, the Müllerian duct, which normally would have developed into female genitalia, degenerated partially, and the Wolffian duct, which normally would have degenerated, began to develop into male genitalia.

Jost's experiment indicated that the sex differentiation of a gonad is determined by its sex chromosomes, and that the sexual characteristics of other tissue are determined by the gonads, not by the chromosomes in the tissues themselves. Jost also showed that in the absence of either gonad, the fetus develops as a female. Female development, then, is apparently a "default" pathway that can be overridden to produce a male.

Studies by C. Ford, P. Jacobs, and co-workers in 1959 demonstrated the importance of genes on the X and Y chromosomes as sexual determinants by documenting the sexual phenotypes of humans with abnormal chromosomal constitutions. Errors in meiosis can produce sperm or egg cells that have abnormal numbers of sex chromosomes. Upon fertilization, these cells develop into embryos with their own aberrant sex chromosome dosage.

Cells in individuals with Turner's syndrome contain a single copy of the X chromosome and no copies of the Y chromosome. These "XO" individuals develop as females, although their ovaries are nonfunctional. This demonstrates that just a single copy of the X chromosome is sufficient to direct most female sex development.

The reciprocal condition, "YO," with no X chromosome present, has not been documented in humans, as X chromosomes contain genes necessary for an embryo's survival. Individuals with Klinefelter's syndrome (XXY), however, develop as phenotypic males, although they produce no sperm. This indicates that a single copy of the Y chromosome is sufficient to override the female developmental program and promote most male development.

Such observations led to speculation that the Y chromosome contains a "testis-determining factor" necessary to activate development of the male gonads. Several genes on the Y chromosome were suggested as possible testis-determining factors but ultimately rejected. In 1990 Peter Goodfellow and coworkers at the Human Genetics Laboratory in London, England, studied a group of sex-reversed XX males. Such individuals develop as phenotypic males despite being XX individuals.

The researchers discovered that the XX males had a small segment from a Y chromosome incorporated into one of their X chromosomes. This same segment was found to be missing from the Y chromosome of a group of sex-reversed XY individuals, who developed as phenotypic females. The segment acted as a testis-determining factor, as its presence was correlated with the activation of male development. DNA sequencing of the segment identified a gene that was named "SRY" from the description "sex-determining region of the Y chromosome."

SRY's Function.

Studies in mice have supported SRY's role as a primary determinant of male development. The mouse homolog of SRY (Sry) is expressed in developing gonads in males but not females. It is present during but not after testis differentiation. Finally, experiments have been conducted where introducing the SRY gene into the genomic DNA of embryonic female (XX) mice causes some of them to develop as males.

Despite the clear causal relationship between this gene and male development, the specific mechanisms involved are unclear. The SRY protein is similar to "high-mobility group" proteins, which regulate the transcription of other genes. Its structure contains a domain that can bind to specific target DNA sequences. Mutations to this domain, which reduce SRY's ability to bind correctly to DNA, are frequently observed in XY individuals that develop as females.

SRY could conceivably function by activating genes involved in testicle differentiation, by repressing genes involved in ovary development, or by doing both of these things. To discriminate among the possibilities, it is necessary to know more about the next level of genes in the developmental cascade, SRY's targets. Several possible direct targets of SRY have been proposed. Most notable is the SOX9 gene, which also encodes a high-mobility group protein that is known to promote male differentiation and which is expressed in the developing male gonad immediately after SRY is first expressed.

Female Development as the Default.

When Jost removed the gonads from embryonic rabbits, the embryos that were XX as well as those that were XY developed as females, though they lacked internal genitalia. This finding emphasized that gonads are critical to secondary sex determination and in the absence of male-specific hormones, female characteristics develop even in an XY individual.

As noted above, individuals with only a single copy of the X chromosome in each cell can survive, and they develop as females. Their ovaries develop normally at first but degenerate around the time of birth, resulting in a sterile adult. Hence a single X chromosome suffices for sex determination, but two copies are needed for ovary maintenance.

One explanation is that the female developmental program is the default, with embryos developing as females unless there are alternative instructions. SRY is a major switch gene required for male development, and only a gonad whose cells contain a copy of SRY will differentiate into a testicle.

Despite intensive searching, no major switch gene has been identified for the female developmental pathway. One candidate, DAX1, was proposed as the main ovarian differentiation gene principally because it was found to be duplicated on the X chromosomes of two XY siblings who developed as females. However, experimentally disrupting the mouse homolog of DAX1 had no effect on the sex determination, maturation, or fertility of female XX mice.

Instead of having a positive regulatory role, DAX1 appears to be antagonistic to SRY's function. When DAX1 is present in two copies, as in the XY sisters, it apparently disrupts SRY function sufficiently to prevent initiation of the male developmental program. These observations are consistent with the idea that the female sex determination pathway is the default option.

Sex determination and differentiation occur in virtually all complex organisms, but the mechanisms used by various animal classes, and even by various vertebrates, differ significantly. Birds, for instance, lack a clear homolog of SRY. In birds it is the female, rather than the male, that has two different sex chromosomes, with males being ZZ, and females ZW. In many reptiles, environmental conditions, rather than genetic factors, are the primary determinant of sex. The temperature at which eggs are incubated determines sex in some lizard, turtle, and alligator species.

In both the fruit fly Drosophila melanogaster and the nematode Caenorhabditis elegans, the primary sex determination mechanisms and the molecular cascades controlling sexual differentiation have been studied extensively. Primary sex determination in these animals does not involve the Y chromosome but instead is determined by the ratio of the number of X chromosomes to autosomal (nonsex) chromosomes. By examining individuals with unusual numbers of various chromosomes it has been determined that in Drosophila those with one or fewer X chromosomes per diploid autosome set develop as males while those with two or more X chromosomes develop as females. Individuals with intermediate ratios such as those with two X chromosomes and a triploid set of autosomes develop as intersexes with both male and female characteristics. Although this ratio serves as the primary determinant of sex in both of these organisms, the specific gene products that influence this ratio assessment are different, demonstrating that different molecular mechanisms can be used for a similar purpose.

There is also significant variability in the strategies by which the outcome of sex determination is communicated to the various tissues that undergo sexual differentiation. In humans and most other mammals, the presence or absence of SRY protein in cells of the gonad specifies their sexual differentiation and which hormones are secreted by the gonad to direct the sexual differentiation of most other cells in the individual.

In Drosophila hormones have little effect on sexual differentiation. Instead, with only a few exceptions, each cell decides its sex independently of other cells and tissues. This "cell autonomous" mechanism is demonstrated in experimentally produced mosaic organisms called gynandromorphs ("male-female forms") in which some cells are XX (female) and others XO (male). Such individuals develop into adults with a mix of male and female cell types that match each cell's genotype. The lack of evolutionary conservation of sex-determining mechanisms among animals is particularly interesting because of the similarities that exist in other major switch genes for basic developmental processes.

Jeffrey T. Villinski

and William Mattox

Bibliography

Berta, Philippe, et al. "Genetic Evidence Equating SRY and the Testis-Determining Factor." Nature 348 (1990): 448-450.

Cline, Thomas W., and Barbara J. Meyer. "Vive la Difference: Males vs. Females inFlies vs. Worms." Annual Reviews of Genetics 30 (1996): 637-702.

Gilbert, Scott F. Developmental Biology, 6th ed. Sunderland, MA: Sinauer Associates,2000.

Hodgkin, Jonathan. "Genetic Sex Determination Mechanisms and Evolution." BioEssays 4 (1992): 253-261.

Sinclair, Andrew H., et al. "A Gene from the Human Sex-Determining Region Encodes a Protein with Homology to a Conserved DNA-Binding Motif." Nature 346 (1990): 240-224.

Zarkower, David. "Establishing Sexual Dimorphism: Conservation amidst Diversity?"Nature Reviews Genetics 3 (2001): 175-185.

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