Male Sex Differentiation

FIGURE 14-15 Schematic diagram of male and female sex determination and differentiation. The key contribution of the SRY gene or testis-determining factor is emphasized on the right for the male; see also Figures 14-17 and 14-18 for additional details. Modified from Grumbach, M. M. (1967). "Biologic Basis of Pediatric Practice" (R. E. Cooke, ed.), p. 1060. McGraw-Hill, New York.

In the absence of the SRY gene, female sex differentiation will lead to conversion of the indifferent gonad anlage into ovaries and to the regression of the wolffian ducts. Thus, the development of the female reproductive tract requires no hormonal stimulation from either ovaries or testes.

3. SRY or Testis-Determining Factor

The recent discovery of the SRY gene which codes for a protein that mediates testicular organogenesis has provided insight into one of the most challenging problems of biology; namely, the molecular basis of sex determination. The SRY gene is located on the Y chromosome. The SRY human gene codes for a DNA-binding protein that has an 80-amino-acid domain similar to that present in "high-mobility group" (HMG) proteins. This DNA-binding domain interacts specifically with high affinity to the DNA sequence AACAAG and causes bends in the DNA.

Importantly, the SRY gene-derived protein interacts with the promoter of two sex-specific genes: (a) the cytochrome P450 aromatase which mediates the conversion of testosterone to estradiol; and (b) Miillerian inhibitory factor (MIF) which mediates Miillerian duct regression, effectively blocking the development of female sex organs. These concepts are illustrated in Figures 14-17 and 14-18. Thus, the combined actions of the SRY protein ensures that the fetus has access to adequate quantities of the male steroid hormone testosterone and, at the same time, promote the regression of the Miillerian ducts which are the precursors of the female sex organs. In this context it is important to appreciate that a fetus (male or female) in its uteroplacental environment is continuously exposed to the female estrogen (see Figure 14-10).

This model was validated by introduction of a 14-kb DNA fragment containing mouse SRY into mouse embryos by microinjection into fertilized eggs. When an XX female embryo was injected with the

figure 14-16 Schematic diagram of male (Wolffian duct) and female (Müllerian duct) differentiation. Testosterone stimulates Wolffian duct development, but has no effect on Müllerian duct inhibitory factor (MIF). Modified from Grumbach, M. M. Styne, D. M., Wilson, I. D., and Foster, D. W. (1992). "Williams Textbook of Endocrinology" Philadelphia, PA.

SRY-DNA, the phenotype was an XX male with functional testes that were morphologically indistinguishable from those of XY male mice.

Differentiation of the male indifferent gonad anlage occurs as a consequence of the presence of the SRY and produces functional testes. With the appearance of the fetal testes (by week 7 of embryo life), two hormones are secreted:-anti-Mullerian hormone and testosterone. The existence of a Miillerian duct-inhibiting factor (MIF) (or the anti-Mtillerian hormone) had been inferred from studies where castrated male fetuses or normal female fetuses treated with androgens did not result in regression of the Miillerian ducts. This observation led to the suggestion that there must be two testes-derived hormones required for complete mascu-linization of the internal reproductive tract: testosterone and a factor designated anti-Mtillerian hormone. This suggestion is supported both by clinical studies of the syndrome of testicular feminization as well as by studies employing antiandrogens (see Figure 1213), where it has been observed that these compounds blocked the ability of the testes to induce the differentiation of the Wolffian duct, but did not block the ability of the testes to induce the regression of the Miillerian ducts.

4. Miillerian Inhibitory Factor (MIF)

Miillerian inhibitory factor (MIF) is the gonadal hormone that mediates regression of the Miillerian ducts during male embryogenesis (see Figure 14-14). MIF is a 140-kDa disulfide-linked homodimer protein that is a member of the transforming growth factor (TGF-/3) multigene family of glycoproteins that includes the inhibins and activins (see Figures 12-6 and 14-18). The proteins of this gene family are all biosynthesized as dimeric precursors that require posttranslational processing for activation, as well as cleavage and dissociation to release functional C-terminal fragments.

MIF is expressed in the Sertoli cells of the testis. Human MIF is synthesized as a highly conserved protein of 536 amino acids with a 24-amino acid leader sequence. This protein is "activated" by cleavage at arginine-427 to yield 57.5- and 12.5-kDa fragments. The 12.5-kDa fragment of MIF is the biologically active protein.

The Leydig cells of the testes (see Chapter 12) are the principal site of steroidogenesis, leading to the production of testosterone. Testosterone, after further metabolism in target cells by the 5a-reductase enzyme to dihydrotestosterone, functions as a steroid hormone to cause differentiation of the Wolffian ducts into the

Y chromosome

SRY gene sry protein

Repressor

Inducer

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