Molecular determinants of mammalian sex

Abstract

Mammalian male sex determination is controlled by a complex hierarchy of gene regulatory proteins and hormones, which promote male gonadal development and regression of the female primordia. At the core of this pathway lies the SRY protein, the master developmental switch for testicu- lar differentiation and hence, the male sex. The three-dimensional struc- ture of the SRY-DNA complex suggests a model of developmental gene regulation in which proteins that alter DNA structure and promote the as- sembly of higher-order nucleoprotein complexes play an essential role in the timing of cell specialization events. leads directly to the development of the testes, and thus, to male sex. Regulated expression in the undifferentiated gonad Three gene products appear to play regulatory roles in the development of the undifferentiated gonad, namely the Wilms' tumor suppressor protein WT1 ~ef. 1), the orphan nuclear receptor protein SF-1 ~ef. 2) and a high mobility group (HMG) family member, which is closely related to SRY and known as SOX9 ~ef. 3)(Fig. 1). Each of these proteins possesses a sequence-specific DNA-binding domain and a putative protein-protein interaction domain, attributes that suggest that these pro- teins regulate transcription. Expression patterns for the genes encoding these proteins indicate that their influence is exerted before the appearance of morphological differences between the sexes in the developing gonad. IN MAMMALIAN SEXUAL differenti- ation, male and female developmental pathways are controlled by the presence or absence of hormones, which are pro- duced by the male and female gonads in the developing fetus. Before hormonal secretion, XX and XY embryos develop two pairs of genital ducts associated with the undifferentiated gonads. The Miillerian ducts have the potential to differentiate into the fallopian tubes, uterus, cervix and upper vagina of the female reproductive tract. The Wolffian ducts become the vas deferens, epi- didymis and seminal vesicles of the male reproductive tract. Consequently, for normal male or female development to occur, one genital duct system must differentiate while the other must regress (Fig. 1). Regression of the female pathway is achieved by the production of Miillerian inhibitory substance (MIS) (also known as the anti-M011erian hormone) in the fetal testicular Sertoli cells. Subse- quently, testosterone, produced by the Leydig cells of the testes, induces dif- ferentiation of the Wolffian ducts into male reproductive organs. In the ab- sence of testes, and therefore in the ab- sence of both MIS and testosterone, the Wolffian ducts passively regress, creat- ing a permissive environment for the M. H. Werner, J. R. Huth, A. M. Gronenborn and G. M. Clore are at the Laboratory of Chemical Physics, Building 5, National institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0520, USA.