Book Viewer

Short Contents | Full Contents | Other books @ NCBI

Modern Genetic Analysis Chapter 16. The Genetic Basis of Development
Sex Determination in Mammals: Coordinated Control by the Endocrine System

An analysis of sex chromosome aneuploids demonstrates that mammalian sex determination and differentiation are quite different from those of Drosophila (see Table 16-2). An XXY human is phenotypically male, with a syndrome of moderate abnormalities (Klinefelter syndrome; see Figure 8-13). XO humans have a number of abnormalities (Turner syndrome; see Figure 8-11), including short stature, mental retardation, and mere traces of gonads, but they are clearly female in morphology. These data are consistent with a mammalian sex determination mechanism based on the presence or absence of a Y chromosome. Without a Y, the person develops as a female; with it, as a male.

Mammalian Reproductive Development and Endocrine Organ Control

In contrast with flies, each individual human cell does not make an independent determination of its sex. Humans mosaic for XX and XY tissues typically have a generalized appearance characteristic of one or the other sex. The observation of nonautonomy in mammalian sex determination can be understood in view of the biology of the reproductive system: sex-specific phenotypes are driven by the presence or absence of the testes.

The gonad forms within the first 2 months of human gestation. Primordial germ cells migrate into the genital ridge, which sits atop the rudimentary kidney. The chromosomal sex of the germ cells determines whether they will migrate superficially or deeply into the gonadal ridge and whether they will organize into a testis or an ovary (Figure 16-6). If they form a testis, the Leydig cells of the testis secrete testosterone, an androgenic (male-determining) steroid hormone. (Recall the discussion of steroid hormone receptor transcription factors in Chapter 14.) This hormone binds to androgen receptors. These receptors function as transcription factors; their transcription-factor activity, however, depends on binding to their cognate hormone. Thus, the androgenreceptor complex binds to androgen-responsive enhancer elements, leading to the activation of male-specific gene expression. In chromosomally female embryos, no Leydig cells form in the gonad, no testosterone is produced, androgen receptor is not activated, and the embryos continue along the default female pathway of development. Hence, it is the presence or absence of a testis that determines the sexual phenotype, through the endocrine release of testosterone. Indeed, in XY embryos lacking the androgen receptor, development proceeds along a completely female pathway even though the embryos have testes (see Genetics in Process 16-2).

Setting the Switch in the On or Off Position

What initiates the sex determination pathway? Molecular genetic analysis has focused on identifying the locus on the Y chromosome that drives testis formation. This hypothetical gene has been called the testis-determining factor on the Y chromosome (TDF in humans, Tdy in mice) and is now known to be the same gene as the SRY (humans)~Sry (mice) gene, first identified through its gain-of-function dominant sex-reversal effect in which heterozygous mutant XX individuals develop as phenotypic malessee Genetics in Process 16-2). Furthermore, because the wild-type SRY~Sry gene is on the Y chromosome, we can easily understand how the onoff switch is set. The wild-type XY individual has an SRY~Sry gene, which causes the male shunt pathway to be activated, whereas the normal XX individual lacking SRY~Sry remains in the female default pathway.

How does SRY~Sry contribute to sex determination? The SRY~Sry protein is a transcription factor and is expressed in the primitive male gonad. Exactly how the SRY~Sry protein initiates testis formation is not understood. However, with the SRY~Sry protein sequence in hand, many avenues for answering this and other age-old questions about the biological basis of sexual phenotype can be pursued.

MESSAGE
In mammals, a Y chromosome gene encodes a transcription factor that causes the gonad to become a testis. The testis serves as a command organ that, through testosterone release, directs male phenotypic development throughout the body.

© 1999 by W. H. Freeman and Company. All rights reserved.